drug hypersensitivity syndrome ( dhs ) refers to a severe , potentially life - threatening , drug reaction . to better individualize this drug reaction , the term " drug rash with eosinophilia and systemic symptoms ( dress ) syndrome " has recently been used . fever , rash , lymphadenopathy , and internal organ involvement with marked eosinophilia constitute the main manifestations . the most frequently involved organ is the liver , followed by the kidney and lungs . the most frequently incriminated drugs are anticonvulsant , sulfonamides , dapsone , allopurinol , minocycline , and gold salt . the pathophysiology of dress syndrome remains unclear , but a defect in detoxification of causative drug , immunological imbalance , and infections such as human herpes virus type 6 ( hhv 6 ) have been suggested ( 2 ) . the overall mortality in dress is about 10% and occurrs in patients with severe multi - organ involvement ( 1 ) . we report here a case of dress syndrome induced by celecoxib and anti - tuberculosis ( tb ) drugs including isoniazid , rifampicin , ethambutol , and pyrazinamide in a patient presented first as knee joints pain . a 29-yr - old woman with no prior known medical illness presented on march 2004 with an oral ulcer and knee joint pain . celecoxib was prescribed by a rheumatologist on 17 march under the suspicion of arthritis . during the course of routine clinical examination , she was treated with isoniazid , rifampicin , ethambutol , and pyrazinamide from march 25th . on april 28th ( 34 and 42 days after the initiation of anti - tb drugs and celecoxib , respectively ) , she was hospitalized due to jaundice and hepatomegaly . on admission , her temperature was 38 , blood pressure was 90/60 mmhg , and heart rate was 90 beats per min . she had an exanthematous rash on her trunk and limbs with some pustules ( fig . 1 ) , decreased bibasilar lung sound , icteric sclera , hepatosplenomegaly , cervical lymphadenopathy , and posterior pharyngeal wall injection . blood cell counts showed hemoglobin 12.4 g / dl , leukocyte count 19,990/l ( polymorphs 45.6% , lymphocytes 28.4% , and eosinophils 12.4% [ upper limit of normal ( uln ) 6% ] ) , and platelet count 261,000/l . on her peripheral blood smear , neutrophilic leukocytosis with eosinophilia was noted without atypical lymphocytosis . serologic tests for viral infections including hepatitis a and b , epstein - barr virus , human immunodeficiency virus , and cytomegalovirus were negative . auto - antibody screening revealed negative antinuclear antibody ( ana ) and anti - smooth - muscle antibody ( sma ) . a skin biopsy ( fig . intravenous methylprednisolone ( 1,000 mg daily ) for dhs and antimicrobial therapy ( intravenous ceftriaxone 2 g daily and amikacin 1 g daily ) for pneumonia were administered for 5 days , followed by oral prednisone 75 mg daily and ursodeoxycholic acid 200 mg three times daily . she presented with a rash on forearm , sore throat , myalgia , swallowing difficulty , and dyspnea . over the next 3 days , she was febrile up to 38 , and the rash extended to whole body with vesicle and pustule formation . the ct scan of abdomen showed hepatomegaly with perihepatic fluid collection . a bone marrow biopsy disclosed moderate hypercellular marrow with diffuse infiltration of eosinophils . the diagnosis of a recurrent dress syndrome was made , and methylprednisolone 1,000 mg daily was infused intravenously for 3 days . on day 4 of readmission , myalgia and swallowing difficulty became more profound and muscle weakness developed . her serum creatine kinase ( ck ) increased up to 18,943 iu / l ( uln 217 intravenous cyclosporine 100 mg daily and oral methylprednisolone 60 mg daily were initiated . however , respiratory muscle weakness exacerbated requiring mechanical ventilatory support with intravenous immunoglobulin ( ivig ) infusion ( 1 g / kg / day for 2 days ) on day 8 of readmission . after 2 weeks of mechanical ventilation , her respiratory function improved and the ventilator was weaned . at that time , a trans bronchial lung biopsy disclosed chronic granulomatous inflammation without significant eosinophilic infiltrate and a sputum afb stain revealed a positive finding . anti - tb treatment with second - line drugs ( cycloserine 500 mg daily , ofloxacin 400 mg daily , prothion - amide 250 mg daily , and streptomycin 1 g five times weekly ) was restarted on june 12th , and cyclosporine was discontinued on june 27th . g / kg / day ] ) of ivig , skin lesions and liver function improved . the prednisone was gradually tapered to 40 mg daily , and the patient was discharged on july 9th . over the next two months , the prednisone dosage was reduced to 20 mg daily and an azathioprine ( azt ) 50 mg daily was added on august 27th because her serum alanine aminotransferase ( alt ) level was fluctuating and we worried about the side effect of long - term steroid therapy in the patient with tb . two weeks after initiation of azt , she had a return of fever , up to 37.6 , jaundice , and a tender liver . laboratory findings at the third admission showed a cholestatic pattern , which was common in azt toxicity ( table 1 ) . azt was stopped on september 12th , and only oral prednisone was maintained at a dosage of 10 to 20 mg daily with one more cycle of ivig . afterwards , the serum alt level became normalized and complete resolution of all symptoms was achieved 14 months after discontinuation of the celecoxib and first line anti - tb drugs . four weeks after discontinuation of the prednisone , patch - testing was performed with the celecoxib and first - line anti - tb drugs to evaluate a causal relationship . the results showed diffuse erythematous rash around the celecoxib , rifampicin , and ethambutol at day 2 . then , the rash was localized to the celecoxib and ethambutol at day 4 , and it was more prominent near the celecoxib ( fig . her episode was more likely induced by the celecoxib which probably played a major contributory role , and other first - line anti - tb drugs played a minor contributory role . her liver function had been completely normalized without recurrence of symptoms , and follow - up lung ct also showed complete resolution of pulmonary tb . clinical features were typical : fever , lymphadenopathy with pharyngitis , rash followed by exfoliative dermatitis , hypereosinophilia > 1,500/l , and visceral involvement ( hepatitis and pneumonitis ) . the symptoms began 34 and 42 days after the introduction of anti - tb drugs and celecoxib , respectively , in our patient . recently , two cases of severe drug hypersensitivity syndrome due to celecoxib have been reported ( 3 ) . in both cases , in the first 2 yr of marketing , the reporting rate for stevens - johnson syndrome / toxic epidermal necrolysis with celecoxib was 6 cases per million person - years of use ( 4 ) . the reporting rate was somewhat higher than the background rate of 1.9 cases per million population per year . in our patient , celecoxib was not suspected at first as the causative drug , but in the patch test it showed stronger reaction than other anti - tb drugs . celecoxib , a selective cyclo - oxygenase-2 inhibitor , is a diaryl - substituted pyrazole derivative containing a sulfonamide substituent . the aromatic amine portion of the sulfonamide is considered to be critical in the development of hypersensitivity syndrome . since celecoxib does not contain the aromatic amine , adverse reactions such as hypersensitivity syndrome and toxic epidermal necrolysis would not be expected to occur at the same frequency as they do with sulfonamides . reports showing lack of cross - reactivity balance the few case reports suggesting cross - reactivity ( 5 ) . in the present case , we also considered the possibility of transferring the aromatic amine portion from anti - tb drugs to celecoxib , but we did not verify such a reaction in vitro . our patient 's patch tests were positive to both celecoxib and ethambutol . in the test , rifampicin also showed positive reaction on day 2 but disappeared on day 4 , then interpreted as an irritant reaction . however , the patch test result is not a confirmative one , and the rifampicin allergy with a negative patch test also has been reported previously ( 6 ) . ethambutol is a relatively safe drug . in a study by pitt ( 7 ) , there were less than 2% of adverse reactions in the 2,000 patients who received 15 mg / kg ethambutol . skin reactions due to ethambutol included hair loss , urticaria , erythema multiforme , angioedema , hyperhidrosis , skin striae , bullous eruptions , and exfoliative dermatitis ( 8) . but a severe cutaneous reaction of toxic epidermal necrolysis associated with ethambutol has been reported ( 9 ) . in a review of the literature clinical and pathologic findings of our patient were consistent with eosinophilic polymyositis ( em ) . eosinophilic myositis is a clinically and pathologically diverse group of inflammatory muscle diseases associated with blood and/or tissue eosinophilia ( 10 ) . the etiologies of eosinophilic myopathy include parasitic infection , vasculitis , malignancies , and idiopathic hypereosinophilic syndrome . an increase in eosinophil production and activation mediated by cytokines like interleukin ( il)-5 are thought to play an important role . elevated muscle il-5 induces local accumulation of eosinophils and the subsequent release of eosinophilic granular proteins . this eosinophilic degranulation is blocked by cyclosporin a and prednisone ( 11 ) . in the same way , internal organ involvement by eosinophil infiltration in dress syndrome systemic corticosteroids can inhibit the effect of il-5 on eosinophil accumulation and reduce the symptoms of dress syndrome ( 12 , 13 ) . in the present case , respiratory muscle weakness progressed resulting in the respiratory failure despite the cyclosporine infusion . ivig with prednisone was administered after the onset of myositis , and the respiratory function resumed with the resolution of dress syndrome and polymyositis . in the previous reports on recurrent dress syndrome , ivig administration showed improvement ( 14 ) . after complete resolution of our patient 's symptoms , laboratory tests for anti - hhv 6 igg antibody showed positive reaction but the polymerase chain reaction for hhv6 dna was negative . so the confirmation of exact association with hhv6 was not made . if hhv6 reactivation was a possibility , our patient 's recovery after ivig therapy could be explained . although the mechanism of ivig treatment in dress remains unknown , the therapeutic effects might be dependent on functional capabilities of anti - virus igg contained in ivig . so far , the only undisputed way to treat severe dhs is prompt withdrawal of the offending drug . systemic corticosteroid administration is classically reported in the case of organ- or life - threatening disease ( 15 ) . in a severe dhs as in present case , provocation test is not ethically recommended . also , in such a case which involves multiple complexed drugs , patch test may be a useful method for detecting the culprit drugs ( 16 ) . this approach has been advocated in previous reports on dress syndrome ( 17 , 18 ) . in conclusion , we report here a case of dress accompanying em , the cause of which might be associated with both celecoxib and ethambutol according to the patch test . celecoxib and ethambutol can be added to the list of drugs causing dress syndrome , but further investigations including lymphocyte toxicity assay might be needed to confirm the causality .
drug rash with eosinophilia and systemic symptoms ( dress ) syndrome reflects a serious hypersensitivity reaction to drugs , characterized by skin rash , fever , lymph node enlargement , and internal organ involvement . 
 so far , numerous drugs such as sulfonamides , phenobarbital , sulfasalazine , carbamazepine , and phenytoin have been reported to cause the dress syndrome . 
 we report a case in a 29-yr - old female patient who had been on celecoxib and anti - tuberculosis drugs for one month to treat knee joint pain and pulmonary tuberculosis . 
 our patient 's clinical manifestations included fever , lymphadenopathy , rash , hypereosinophilia , and visceral involvement ( hepatitis and pneumonitis ) . during the corticosteroid administration for dress syndrome , swallowing difficulty with profound muscle weakness 
 had developed . 
 our patient was diagnosed as dress syndrome with eosinophilic polymyositis by a histopathologic study . 
 after complete resolution of all symptoms , patch tests were positive for both celecoxib and ethambutol . 
 although further investigations might be needed to confirm the causality , celecoxib and ethambutol can be added to the list of drugs as having the possibility of dress syndrome .