1 cases of drug hypersensitivity syndrome caused by phenobarbital

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1 cases of drug hypersensitivity syndrome caused by phenobarbitalWang Yongmei, Zou Zhiqiang, Sun Jing, Ding KunDepartment of infectious dise


1 cases of drug hypersensitivity syndrome caused by phenobarbital

Wang Yongmei, Zou Zhiqiang, Sun Jing, Ding Kun

Department of infectious diseases hospital of Yantai City, Yantai City, six Department of information science, infectious disease hospital of Yantai City Infectious Disease Hospital of Yantai city hospital for infectious diseases, two, zip code 264001


With the surname Wang, male, 21 years old, with a history of more than 10 years history of epilepsy, usually have a big attack, C Masi Bing had long been taking treatment, before the onset of the last 1 months for Phenobarbital and sodium Bromide Tablets, Vanillin Tablets, zhenxiantablets treatment. The incidence of 3-4 days without predisposing cause fever, fatigue, not activities associated with anorexia, with oliguria, yellow urine, like tea color. In the local hospital laboratory abnormal liver function, anti infection, symptomatic treatment of ceftriaxone (specific and unspecified), poor effect. Half a day before to the hospital because of fever, oliguria, suspected hemorrhagic fever, transferred to our hospital, outpatient service with "fever, abnormal liver function of unknown origin in 2012.4.12 hospital.

After admission, blood routine examination: WBC10.2 * 109/L, N35%, L41%, M15%, E6.5%, B2.3%, HB, 172g/L, PLT 143 * 109/L. Liver function: alanine aminotransferase (ALT): 2270U/L, aspartate aminotransferase (AST) 869U/L, gamma glutamyl transferase (GGT) 393U/L, alkaline phosphatase (ALP) 290U/L, 43g/L (A), albumin globulin (G) 23g/L, total bilirubin (TB): 45umol/L, direct bilirubin (DB) 35umol/L, adenosine deaminase (ADA) 63.4IU/L, bile acid (TBA) 49.8 mol/l. Blood fat: 1.88 mmol/l (TG), high density lipoprotein (HDLC) 0.55 mmol/l, very low density lipoprotein (VLDL) 0.38 mmol/l, apolipoprotein A (LPa) 383 mg/l; hepatobiliary five: prealbumin (PA 180 mg/l), lactate dehydrogenase (LDH) 569.3 mol/l, glutamate dehydrogenase (GLDH) 58IU/L two, glycylproline dipeptidylaminopeptidase (GPDA) 191.6U/L; HBVM: Anti-HBs16.01mIU/ml, the negative. Coagulation combination: PT15.10S, PTA67.40%; T lymphocyte subsets: CD3+CD4+ 15.8%, CD3+CD8 +52.95%, CD4/CD8 0.30, CD3 - CD19+ 0.4%. Autoantibody negative. Electrocardiogram: sinus rhythm. Abdominal ultrasound: 1, right hepatic lobe bile duct stones, gallbladder inflammation, 2 splenomegaly in 3. Second days after admission, the patient had a rash, red maculopapule, tip to the grain size of samples, no blister, skin rash between normal, press fade, no scaling, mostly in the trunk and limbs gradually to the development (see Fig1, 2). Inosine and Glucurolactone, glutathione, matrine, hepatoprotective drugs such as jaundice treatment, no application of Phenobarbital and sodium Bromide Tablets. The condition did not improve, gradually increase, still have a fever, the temperature continues to rise, the highest to 40 DEG C, chills, chills, rash gradually increased, like the measles, all over the body and limbs, and spread to the hands and feet. The rash develop gradually to the wheal, then gradually scaling. The patient's condition gradually increased, abdominal pain, shock, shock treatment. Blood 2012.4.18 increased gradually, the review of blood: WBC24 * 109/L, N38%, L%35%, M20%, B%1.01%, E4.94%, RBC4.84 * 1012/L, HGB141g/L, PLT 61 * 109/L. Atypical lymphocyte 7%. Hemagglutination: PTA 34%. ALT:909U/L: AST:372U/L GGT, liver 140U/L, ALP 184U/L, A/G 26.7/12.5g/L, TB:133umol/L DB:107umol/L. Biochemistry: NA134mmol/l, GLU 4.27mmol/L, CRP 33.9mg/L, BUN 10.2mmol/L, Cr 63.8umol/L. PTA41%. Myocardial enzyme spectrum: LDH 855U/L, CKMB 53U/L, CK 66.9U/L. Considering the presence of infection in patients, the treatment of anti infective therapy was given to the Finn and cola. Again the blood test can be found in the abnormal lymphocyte 10%, examination can touch the right neck and right axilla, a number of pieces of the right inguinal superficial lymph nodes, soft, no tenderness. Suspected of blood system disease, the possibility of lymphoma. 2012.4.18 went to Yantai Yuhuangding Hospital to continue treatment.

Blood routine examination in Yantai Yuhuangding Hospital: WBC19 * 109/L, N46%, L%10%, M4%, E7%, RBC5.25, HGB146g/L, PLT * 1012/L, 61 * 109/L, 33% abnormal lymphocytes. ALT:851U/L: AST:322U/L GGT, liver 186U/L, ALP 180U/L, A/G 23.3/20.3g/L, TB:191 umol/L DB:147umol/L. LDH 1026U/L. Autoantibodies ANA, SSA, SSB, anti JO-1, anti DNA antibody were negative. The results of bone marrow examination showed that the bone marrow hyperplasia was active, the ratio of red to red was 11.3:1, and the activity of granulocyte proliferation was 56.5%, the cell maturation was delayed and the ratio of eosinophils was increased, accounting for 17%. Erythroid hypoplasia, accounted for 5%, accounted for 19% of lymph, mature lymphocytes, abnormal lymphocytes accounted for 17.5%, accounted for 62 of the megakaryocyte and platelet rare. Diagnosis of bone marrow: accord with acute infection of bone marrow. The right cervical lymph node biopsy: lymph node structure, expand the paracortex, mixed small cell and large cell with high endothelial venules, hyperplasia, lymphoid follicles shrink by immunohistochemistry with reactive hyperplasia of lymph node. Immunohistochemical staining: CD20+, CD3+, CD21+, bc1-2-, and Ki67 in the cortical area of the lateral cortex were 50%. T lymphocyte subsets CD4+ 20.16%, CD8+ 57.47%, CD3 85%, CD16+56+ (NK) 0.85%. Abdominal and chest CT showed bilateral pleural effusion and a small amount of ascites, abdominal, retroperitoneal, bilateral axillary, mediastinal lymph node enlargement. A, C, hepatitis E virus antibody markers, EB was negative. Legionella pneumonia mycoplasma IgM, Q IgM, IgM fever and mycoplasma pneumonia IgM, adenovirus IgM, respiratory syncytial virus, influenza virus IgM A type IgM, IgM type B influenza virus, parainfluenza virus 1, 2 and 3 IgM were negative. Toxoplasma gondii IgM, cytomegalovirus IgM, rubella virus IgM, herpes simplex virus IgM were negative. Exclude lymphoma, consider the possibility of viral infection. Application of imipenem, teicoplanin, Diflucan, albumin, globulin, hormone treatment, the disease gradually eased, rash subsided gradually, decreased body temperature, liver function gradually improved, jaundice decreased, PTA increased, 2012.5.6 patients in hospital.

Go home 3 days later, again accompanied by fever, rash, and previous symptoms similar to Shangdong Province-owned Hospital for treatment, after the consultation, suspected of drug hypersensitivity syndrome. Given immunoglobulin and hormone therapy for half a month, improved discharge. To maintain the amount of hormone (prednisone 30mgqd, half month reduction 5mg) with medicine, home.


Drug hypersensitivity syndrome (drug-induced hypersensitivity, syndrome, DIHS) is a kind of specific symptoms of severe drug eruption. The clinical manifestations of acute extensive lesions, fever, lymph node enlargement, multiple organ involvement (hepatitis, nephritis, pneumonia), eosinophilia and mononuclear cells and other hematological abnormalities. At present, it is believed that, in a certain genetic background, the defects of the body's detoxification function of the active metabolite of the drug is one of the causes, and the reactivation of human herpesvirus -6 infection is also involved in the occurrence of the disease. The tissue damage caused by drug and virus reactivation induced by immune hypersensitivity is mainly caused by CD8+ cytotoxic T lymphocytes. The most effective treatment is the combination of hormone and immunoglobulin in the treatment of pathophysiological changes.

Drug hypersensitivity syndrome can be caused by a variety of drugs, including anti epilepsy drugs and antibiotics, allopurinol, non steroidal anti-inflammatory drugs, including common drugs for C Masi Bing, phenobarbital, dapsone etc.. The patients taking the Phenobarbital and sodium Bromide Tablets is a kind of compound preparation, including phenobarbital, sodium bromide, danshen root, Patrinia scabiosaefoliafisch, valerian, mother of pearl, camphor, borneol. The phenobarbital can cause drug hypersensitivity syndrome [1,2].

1994 Roujeau and Stern will have fever, rash, visceral involvement triad of acute or fatal specific adverse reactions known as DIHS[1-3]. The disease as a result of sudden onset, severe illness, easy misdiagnosis, clinical fatal risk [3-4]. Usually after treatment 2-6 weeks (average 3 weeks) after stopping the disease, still can continue to develop, even worse, the lesions are often more than 1 months can be alleviated, typical clinical manifestations of Shuangfeng, may be related to herpes simplex virus type 6 (HHV-6) latent infection on [5]. Its pathogenesis has not yet been clear, the main factors are genetic susceptibility, immune factors, drug factors, viral infection factors. Some people think that DIHS is a kind of delayed hypersensitivity induced by T cell and toxic metabolites. [6]. It has also been suggested that the disease is caused by a combination of drug allergy and reactivation of human herpesvirus (including HHV-6 and HHV-7). [7].

DIHS induced symptoms vary, and can appear a variety of abnormal laboratory examination results, the diagnosis is often difficult, but once the diagnosis, the treatment is relatively easy, and the success rate is high, including immediately suspended allergenic drugs and monitoring of visceral function, systemic corticosteroids and immunoglobulin such as the main method, and key this disease is timely and accurate diagnosis of [8-9]. Research in recent years in Japan, the Japanese Ministry of health proposed diagnostic criteria for a modified version of DIHS [10] in 2002, the increase of the classification, typical and atypical cases include the following: (L) delayed the onset of application of certain drugs, with the rapid expansion of erythema, most patients progress to erythroderma. (2) after the discontinuation of the causative drugs, symptoms in more than 2 weeks. (3) body temperature higher than 38 DEG C. (4) accompanied by liver damage. (5) accompanied by more than one hematological changes: WBC> ll * l09/L; more than 5% of abnormal lymphocytes; eosinophils > L500 * l06/L. (6) enlargement of lymph nodes. (7) reactivation of HHV-6. Typical DIHS has more than 7, atypical DIHS with L ~ 5.

The characteristics of this case is: the application of compound phenobarbital rash after L months, different from ordinary drug eruption. The discontinuation of phenobarbital in 1 months after the rash is still in progress, persistent symptoms. There are two obvious processes. With repeated fever, the highest body temperature reached 40 degrees C. The multi organ with liver, lung, heart damage, severe illness. The blood change obviously: WBC increased significantly, up to 24 x 109/L. Eosinophils increased, up to 1.42X109/L. Abnormal lymphocytes high, up to 33%. The body has multiple enlarged lymph nodes, including abdominal, mediastinum and axillary etc.. Therefore, the patients met the DIHS diagnostic criteria in 6, belong to atypical DIHS. Unfortunately, the patient failed to detect HHV-6. There is a bacterial or viral infectious diseases need to be differentiated with DIHS diseases, such as infectious mononucleosis, severe hepatitis, measles, the adult Still disease, the other lymphomas, such as autoimmune diseases, diseases of the serum. The patient in the course of diagnosis and treatment, had a high degree of suspicion for lymphoma, viral infection and measles, clinicians need to carefully identify, improve awareness of the disease.

Review the case history of patients with application of phenobarbital in the first onset in the treatment process, the patients at the beginning of the rash is not obvious, is not considered to have a fever caused by drugs. When a patient has a significant skin rash, the rash may be considered as a drug allergy. But the patient had stopped taking the medicine, but illness gradually increased, so consider drug rash is unlikely. Investigate its reason, and clinical departments of the disease is not enough understanding. Literature search found that the skin Kone, the disease is more common, other departments of the disease is limited. Through this case, you can let the relevant departments to learn more about the disease, broaden the thinking of clinical diagnosis.

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