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drug reaction with eosinophilia and systemic symptoms ( dress ) syndrome is a rare but life - threatening reaction to drugs such as carbamazepine and allopurinol .
the condition is characterized by skin rashes , fever , hematological disturbances , lymphadenopathy , and organ failure , most probably hepatic dysfunction . to date , only a few cases of valproate - induced dress syndrome have been reported .
we report on the case of a 60-year - old man who had been treated with valproic acid some time before being referred to kowsar hospital , semnan , iran in december 2015 .
he was given valproic acid 1000 mg po , and after 20 days , he had developed widespread rashes , fever , esophagitis , cervical lymphadenopathy , and tender hepatomegaly .
laboratory results at kowsar showed a drop in hemoglobin , in addition to lymphocytosis , thrombocytopenia , and elevated serum transaminases .
only a small number of case reports have described valproic acid - induced dress syndrome ; therefore , the condition is difficult to prevent .
rechallenge with valproic acid should be avoided in patients with a history of reaction to the drug .
drug reaction with eosinophilia and systemic symptoms ( dress ) syndrome is a rare and life - threatening hypersensitivity reaction to drugs .
the incidence of dress is about one in 1,000 to one in 10,000 drug exposures ( 1 ) .
the mortality rate associated with the condition is 10 - 20% , which is chiefly due to severe liver dysfunction and renal failure .
the condition is characterized by the delayed onset of symptoms , which typically occur two to six weeks after the initiation of treatment .
skin rashes , fever , lymphadenopathy , eosinophilia , and involvement of the liver and kidney are very often seen in patients with dress ( 2 ) .
several mechanisms , for example , a genetic predisposition to immune reactions , and the reactivation of viruses like cytomegalovirus , the epstein barr virus , and the herpes virus , are believed to be associated with the pathogenesis of dress .
another proposed causative mechanism is the accumulation of toxic metabolites due to a failure in the metabolism of drugs ( 3 ) .
more than 50 drug types have been reported to cause dress , which include aromatic anticonvulsants ( carbamazepine and lamotrigine ) , antibiotics , sulfa derivatives , analgesics , and antidepressants ( 4 ) .
dress is diagnosed primarily on the basis of the following regiscar criteria : an acute rash , fever above 38c , lymphadenopathy at two sites , the involvement of at least one internal organ , and abnormalities in the lymphocyte and eosinophil counts ( 5 ) .
the usual treatment for dress is discontinuation of the causative drug and the use of corticosteroids .
valproate is an anti - seizure drug and is considered to be the best initial choice .
gastrointestinal upset , sedation , ataxia , and tremor are the most common toxicities of valproate ( 6 ) .
however , in contrast to phenytoin and lamotrigine , very few studies have reported valproate - induced dress syndrome . here , we describe a case of valproate - induced dress syndrome with hepatitis and pleural effusion .
in december 2015 , a sixty - year - old man was referred to kowsar hospital in semnan , iran , which is a specialized , government referral hospital .
the patient was complaining of skin rash , fever , a distended abdomen , and severe pruritus , which had been going on for 10 days .
the report showed that the patient had been admitted to another hospital four months previously complaining of a severe headache .
a subarachnoid hemorrhage ( sah ) was diagnosed by the neurologist and the patient was given valproic acid ( depakene , abbvie , us ) 500 mg po once daily to prevent seizures .
twenty days before admission to our hospital , the dose of valproic acid increased to 1000 mg po once daily .
in addition , he was using 26 units of insulin glargine ( lantus , sanofi aventis , france ) and 22 units of insulin aspart ( novorapid , novo nordisk , denmark ) for three months .
on admission to kowsar hospital , physical examinations showed that the patient was conscious and well nourished , and had no signs of respiratory distress .
he had erythematous maculopapular rashes covering the body , severe pruritus , and no mucosal involvement .
he also had bilateral cervical lymphadenopathy , with lymph nodes of 1  2 cm in size that showed slight tenderness .
based on these findings , the patient was admitted to the department of internal medicine , section 2 , bed number 9 .
the suspected diagnosis of the patient included skin vasculitis , drug eruption , fascioliasis , and churg - strauss syndrome , as well as viral infections such as cytomegalovirus and toxoplasmosis .
the patient was given an antihistamine and hydrocortisone 30 mg po on admission day , and the rash and fever subsided .
the previous treatments , including the insulin and valproic acid , were not stopped . on day 2 ,
purpura and petechia were present on the hands , and a few vesicles were present on the inguinal area and the thigh .
a skin biopsy showed a high infiltration of lymphocytes and scattered eosinophils and neutrophils with focal exocytosis and spongiosis .
mucosal involvement was also present , and esophageal candidiasis was diagnosed by endoscopy ( olympus , japan ) ( figure 1 ) .
fluconazole was initiated to treat the candidiasis ( 200 mg po on diagnosis and 100 mg qd thereafter ) .
due to the patient s consumption of local vegetables , anthelminthic therapy with albendazole ( 400 mg po ) was introduced but did not lead to a response .
due to bilateral costophrenic angle blunting , a chest ct scan ( ge healthcare , usa ) was performed , and showed bilateral pleural effusion ( figure 2 ) .
a significant drop was seen in hemoglobin concentration and platelet numbers , while bone marrow biopsy was negative for blood malignancies .
sonography showed a severe gaseous abdomen suggesting grade 1 fatty liver . according to the regiscar scoring system ,
the patient had a score of six points , which indicated a definitive diagnosis of dress syndrome . on day 10 , dress was diagnosed .
due to unsuccessful treatments with corticosteroids and a rise in hepatic transaminase to more than 1000 iu / l , intravenous immunoglobulin ( ivig ) of 2 gr / kg ( intratect , biotest pharma , germany ) was administered for three consecutive days .
on day 13 , the general condition of the patient was found to have improved . on day 16 , he was discharged with stable laboratory findings and diminished skin rashes ( figure 3 ) .
in addition , the patient s general condition remained satisfactory for the two - month follow - up period .
it is considered a significant complication due to its high rate of mortality . dress syndrome , stevens - johnson syndrome , and acute generalized exanthematous pustulosis are skin eruptions that can be fatal because they lead to life - threatening organ failures .
dress syndrome is characterized by sudden skin rashes , fever , blood disturbances , lymphadenopathy , and involvement of the internal organs , most often the liver and the lungs ( 1 , 2 ) .
liver failure is the main cause of death , and it may vary from hepatocellular and cholestatic damage to fulminant hepatic failure ( fhf ) ( 3 ) .
the reactivation of viruses , genetic predisposition , and defects in the metabolism of drugs have been proposed as possible factors in the pathogenesis of dress syndrome .
it has been demonstrated that regulatory t ( treg ) cells expand at the acute stage of dress , and this functional defect in treg cells could be responsible for the development of autoimmune diseases that may occur months to years after the resolution of dress ( 3 , 7 ) .
the causative drugs most commonly associated with dress are carbamazepine , phenytoin , allopurinol , sulfasalazine , and abacavir ( 4 ) .
cacoub s study showed that of a total of 44 drugs associated with the 172 cases reported between 1997 and 2009 , the most frequently reported causative drug was carbamazepine ( 5 ) . in the vast majority of reported cases of dress ,
it is suggested that aromatic anticonvulsants can initiate dress in individuals with a defect in the epoxide hydrolase enzyme , which can cause an accumulation of arene oxides .
reported a case of dress induced by valproic acid with multiple organ dysfunction ( 9 ) , while arevalo - lorido et al . described a patient with severe dress caused by valproate ( 10 )
discussed the case of a 25-year - old woman with bipolar disorder who experienced dress caused by valproic acid three weeks after the initiation of treatment ( 11 ) .
similarly , bin nakhi et al . described two cases of dress onset . in one case ,
the patient was given carbamazepine , and in the other , the patient received a combination of lamotrigine and valproic acid . for both , the treatments were discontinued and supportive care was administered ( 12 ) .
dress is typically diagnosed using the regiscar criteria , and patients must fulfill three of the four main criteria ( 1 ) .
another method is the japanese consensus group criteria system , which requires seven of the system s nine criteria or all of the first five to be met for a diagnosis to be made ( 3 ) .
case criteria are graded as not met , possibly met , probably met , or definitely met by the regiscar scoring system .
scores of five or more are classified clearly as dress syndrome . in our case , the score was seven points , and the condition was therefore classified definitively as dress syndrome .
as suggested , systemic corticosteroids are reserved to treat severe dress with gross manifestations ; however , due to the high likelihood of relapse , most clinicians prefer to use systemic corticosteroids even for mild forms of dress ( 13 ) . at present , the type and dose of corticosteroid , and the duration of treatment are not conclusive .
interestingly , our case did not respond even to a high dose of corticosteroids . to avoid fulminant hepatitis and to reduce severe symptoms ,
three doses of ivig improved the general condition of the patient . to the best of our knowledge ,
only five cases of valproic acid - induced dress syndrome have been reported so far . however , while dress syndrome is rare , it can be fatal .
therefore , clinicians must be aware of the presence of cross - reactivity between aromatic anticonvulsants and valproic acid .
in addition to corticosteroids , the efficacy of other immunosuppressive agents needs to be further investigated for the treatment of dress .
introductiondrug reaction with eosinophilia and systemic symptoms ( dress ) syndrome is a rare but life - threatening reaction to drugs such as carbamazepine and allopurinol . 
 the condition is characterized by skin rashes , fever , hematological disturbances , lymphadenopathy , and organ failure , most probably hepatic dysfunction . to date , only a few cases of valproate - induced dress syndrome have been reported.case presentationwe report on the case of a 60-year - old man who had been treated with valproic acid some time before being referred to kowsar hospital , semnan , iran in december 2015 . 
 he was given valproic acid 1000 mg po , and after 20 days , he had developed widespread rashes , fever , esophagitis , cervical lymphadenopathy , and tender hepatomegaly . 
 laboratory results at kowsar showed a drop in hemoglobin , in addition to lymphocytosis , thrombocytopenia , and elevated serum transaminases . 
 dress was diagnosed , and corticosteroid therapy was initiated . 
 administration of the culprit drug to the patient was also stopped . 
 intravenous immunoglobulin ( ivig ) improved the general condition of the patient.conclusionsonly a small number of case reports have described valproic acid - induced dress syndrome ; therefore , the condition is difficult to prevent . 
 rechallenge with valproic acid should be avoided in patients with a history of reaction to the drug .