a hypersensitivity reaction ( hsr ) is a host - dependent idiosyncratic adverse drug reaction ( adr ) that can not be predicted by the dose , frequency , or length of the treatment . hsr is defined by the triad of fever , rash , and internal organ involvement [ 16 ] . hsrs occur with an incidence of 1 in 1000 to 1 in 10000 drug exposures , with a mortality rate approaching 10% [ 58 ] . symptoms of hsr can range from general manifestations , such as morbiliform rash , urticaria , angioedema , fever , malaise , anaphylaxis , bronchospasm , and erythema multiforme , to severe cutaneous adverse reactions ( scar ) such as drug - induced hypersensitivity syndrome ( dihs)/drug reaction with eosinophilia and systemic symptoms ( dress ) , and stevens - johnson syndrome ( sjs)/toxic epidermal necrolysis ( ten ) [ 2 , 47 , 911 ] . cutaneous eruptions are reported in the vast majority of dihs / dress cases , often presenting as maculopapular rash or generalized erythematous rash [ 7 , 8 ] . the internal organ most often affected is the liver , with drug - induced liver injury ( dili ) presenting as anomalies in liver function tests or the presence of hepatomegaly . aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) were found to be increased an average of 9 - 10-fold above the upper normal limits in a literature review of 172 dress cases . the presence of serum bilirubin raised > 3 times over the upper limit of normal along with aminotransferase elevations is associated with a more severe set of symptoms than isolated aminotransferase abnormalities alone , an observation known as hy 's law [ 12 , 13 ] . other internal organs , such as kidneys , are less often affected [ 4 , 7 ] . skin rash , liver involvement , high - grade fever , hypereosinophilia , lymphadenopathy , and the increased presence of atypical lymphocytes are symptoms associated with dihs / dress cases classified as maculopapular rash , erythema multiforme , exfoliative dermatitis , acute generalized exanthematous pustular dermatosis - like eruptions , and erythroderma are types of cutaneous manifestations associated with dihs , while mucosal involvement is rare . on the other hand , skin and mucosal involvement characterizes sjs / ten . a further distinction between dihs / dress and sjs / ten is the time to onset of symptoms , which is often delayed ( 4 - 5 weeks ) in the former , while it occurs in the early stages of drug exposure ( approximately 3 weeks ) in the latter . carbamazepine was the drug most often associated with dress among 44 drugs linked to this reaction in 172 cases reported over a period of 12 years . anticonvulsants such as carbamazepine , phenytoin , phenobarbital , lamotrigine , zonisamide , and sodium valproate are the class of drugs most often related to dihs / dress . other pharmaceutical agents , including allopurinol , nonsteroidal anti - inflammatory drugs , chlormezanone , aminopenicillins , cephalosporins , quinolones cycline antibiotics , and antiretrovirals , as well as anti - infective sulfonamides , have also been implicated [ 68 , 11 , 1416 ] . scar development results in patient hospitalization , and the culprit drug is interrupted on the first day of hospitalization . the mean time to recovery was 6.4 weeks in 172 dress cases , while death was recorded in 9 ( 5.2% ) patients . death was connected with a more severe course of reaction , particularly observed in older patients , and often due to liver failure . while the precise mechanism of hsr is unknown , various theories involve the interplay between metabolic and immunologic factors [ 2 , 4 , 6 ] , genetic predisposition , and , more recently , infection with human herpes viruses ( hhv ) , particularly hhv-6 . drug metabolites bind to cellular macromolecules such as proteins , creating covalent adducts that can serve as antigenic stimuli for the immune system [ 4 , 6 ] . several genetic factors are believed to predispose certain individuals to this type of adverse reaction . the subset of the population that is susceptible to hsrs carries defects in drug detoxifying pathways ( e.g. , epoxide hydrolase ) , such that a greater amount of a reactive drug metabolite is produced than that which can be detoxified [ 2 , 4 , 6 ] . additional genetic predispositions that render certain individuals susceptible to hsrs include human leukocyte antigen ( hla ) alleles , which are part of the major histocompatibility complex ( discussed by neuman et al . ) . reactivation of latent viral infections has been linked to the development of more severe hsr symptoms , particularly in the context of dihs / dress . for example , hhv-6 reactivation was associated with more severe organ involvement and a prolonged course of disease in 62 of 100 dihs patients , compared with the remaining 38 patients who did not experience hhv-6 reactivation . in the same study , all five deaths and ten cases of renal failure were observed among the 62 patients with hhv-6 dna detected in the serum . hhv-6 is a lymphotropic dna virus belonging to the betaherpesviridae subfamily [ 19 , 20 ] . while little is known about hhv-6a , hhv-6b infection often occurs during the first 2 years of life and is associated with acute febrile illness in young children and exanthem subitum in infants [ 1926 ] . hhv-6 has been increasingly recognized as a cause of hepatitis and liver failure , as well as increased graft rejection and consequent decreased patient survival [ 2026 ] . following the initial infection , hhv-6b remains present in a latent phase , and infection can be reactivated during episodes of immunosuppression [ 20 , 22 , 24 , 26 ] . inherited forms of both hhv-6a and hhv-6b this condition , known as chromosomally integrated hhv-6 ( cihhv-6 ) , occurs in 0.8% of control populations but is found in approximately 2% of patient populations in europe , united states , and the united kingdom , with a lower rate in japan . cihhv-6 is characterized by the complete integration of the hhv-6 genome into the host germ line genome , such that cihhv-6 dna is found in every nucleated cell in the body [ 24 , 27 ] . persistently high viral copy numbers in whole blood or serum are observed in individuals with this condition [ 28 , 29 ] . the viral genome of cihhv-6 is transmitted vertically in the germline in a mendelian manner . approximately 1% of newborns are diagnosed with congenital hhv-6 , all of which are infected with cihhv-6 , directly or indirectly . in a sample of 43 infants with congenital infection , the majority ( 86.0% ) were born with inherited cihhv-6 , while the remaining ( 14.0% ) were not born with cihhv-6 but became infected with hhv-6 transplacentally from their cihhv-6-positive mothers . the cellular dna damage machinery responds to virus infection and the foreign genomes that accumulate in the nuclei of infected cells . many dna viruses have been shown to manipulate the cellular dna damage response pathways in order to create environments conducive to their own replication . arbuckle et al . showed that hhv-6 dna integrates specifically and efficiently into the telomere sequences of chromosomes . the integrated virus can be chemically activated with trichostatin a , a stimulatory compound known to reactivate latent herpesviruses . active hhv-6 replication is determined by the presence of hhv-6 dna in serum , plasma , or cerebrospinal fluid , or by reverse - transcriptase polymerase chain reaction ( rt - pcr ) in peripheral blood mononuclear cells ( pbmc ) . rt - pcr is the sole technique that allows active hhv-6 replication to be differentiated from inactive cihhv-6 . the present paper reviews recently published case reports of scar ( dihs / dress and sjs / ten ) and dili developed secondary to drug exposure , with a particular focus on the role of hhv-6 reactivation and cihhv-6 presence in the clinical outcome of the reaction . our principal aim is to address the role of hhv-6 reactivation in the course of hsrs , particularly in dili and dihs / dress . in addition , we will focus on the complex cellular responses triggered by hhv-6 reactivation . studies discussed in this paper were selected based on a pubmed search of english language papers published in the last 15 years ( 19972011 ) using keywords such as  hhv-6 and hypersensitivity , hhv-6 reactivation and drug ,   hhv-6 and drug rash ,  and  chromosomally integrated hhv-6 . the selected case reports are part of a larger database of hsr cases with hhv-6 reactivation . in addition , our laboratory has studied hsrs and their mechanisms for the last 25 years , and we discuss the cases based on our experience related to the laboratory and clinical manifestations . following initial infection in early childhood , hhv-6 continues to exist in a latent phase in the body . consequently , hhv-6 dna can be measured in different body compartments in hhv-6-positive individuals without active infection . trace amounts of hhv-6 viral dna were also detected by real - time quantitative pcr in 91 ( 26.8% ) of 339 pediatric patients diagnosed and treated for acute lymphoblastic leukemia . low rates of hhv-6b dna were detected in whole blood ( 8.0% ) , pbmcs ( 16.5% ) , and polymorphonuclear leukocytes ( 10.5% ) belonging to 200 volunteers . the mean observed hhv-6b viral loads were 81  copies/10 cells in whole blood , 62  copies/10 cells in pbmcs , and 34.5  copies/10 cells in polymorphonuclear leukocytes . hhv-6-dna was positive in only 27 ( 39.1% ) blood samples from 69 children undergoing elective tonsillectomy for moderate tonsillar hyperplasia or recurrent streptococcal infection without evidence of acute hhv-6 infection , while evidence of hhv-6 dna was found in 100% of tonsil samples in the same population . the common features of dihs identified in a sample of 7 patients were high fever ( 39c ) in all patients , facial edema in all patients , diffuse lymphadenopathy in 5 ( 71.4% ) patients , hypereosinophilia ( > 0.5  10/l ) in 4 ( 57.1% ) patients , atypical circulating lymphocytes in 4 ( 57.1% ) patients , alt elevated > 3 times the reference level in 5 ( 71.4% ) patients , and hypogammaglobulinemia in 4 ( 57.1% ) patients . the onset of dress took place after a mean period of 25 days ( 5 days6 weeks ) of therapy with the incriminated drug . similar findings are reported in other cohorts of dihs patients [ 15 , 56 ] . several studies suggest that hhv-6 reactivation can only occur in susceptible individuals under conditions of transient immunosuppression , such as those transiently associated with the onset of dihs [ 56 , 57 ] . lower serum igg levels were observed in 10 adult anticonvulsant - induced hsr patients ( mean 745  mg / dl ) compared to 15 controls ( p < 0.001 ) . similarly , circulating levels of b cells were also decreased in dihs patients , compared to controls [ 15 , 57 ] . in susceptible individuals , continuous therapy with anticonvulsants , which have been associated with dihs , moreover , hhv-6 reactivation may occur at the same time , but it can not always be detected in blood , since it takes 24 weeks for antibodies to appear after infection or reactivation . because decreases in circulating igg and b cell levels are not observed with other hypersensitivity conditions such as sjs / ten , depressed levels of igg and b cells can be used as biomarkers for the onset of dihs . hhv-6 reactivation may be partially explained by the immunosuppressive effects of dihs - related drugs . the magnitude of inflammation is often proportional to the clinical manifestations , while hypogammaglobulinemia and hhv-6 reactivation worsen the clinical course of the disease . a more detailed description of disease progression is presented in case reports , some of which are summarized in table 1 [ 3552 ] . edema , predominantly on the face , was observed with a relatively high frequency [ 35 , 37 , 3944 , 4749 , 52 ] , as were lymphadenopathy [ 35 , 36 , 39 , 4143 , 45 , 46 , 4951 ] , hypereosinophilia [ 3540 , 4252 ] , and atypical lymphocytes [ 35 , 36 , 3840 , 42 , 44 , 46 , 47 , 52 ] . internal organ involvement manifested itself largely as liver dysfunction , with elevated levels of liver enzymes [ 3546 , 4850 , 52 ] and cholestatic hepatitis with hepatocellular insufficiency . multiple organ failure was observed in a couple of studies [ 47 , 51 ] , one of which resulted in death . hypogammaglobulinemia , another symptom of dihs , was observed in a number of studies as well [ 35 , 38 , 39 , 45 , 49 ] . the offensive drug is immediately interrupted in dihs patients , and treatment with prednisolone is often used to reverse the condition . symptoms begin to improve gradually , but both fever and skin manifestations often relapse approximately 2 - 3 weeks after the onset of dihs . there is a delay until antibodies to the virus are generated . symptoms relapse coincides with detection of hhv-6 reactivation , measured by circulating anti - hhv-6 antibodies and hhv-6 dna [ 15 , 56 ] . anti - hhv-6 igg levels are elevated after 3 weeks following the onset of the reaction ( time of drug withdrawal ) , but not after 2 weeks [ 58 , 59 ] . increases in hhv-6 dna in pbmcs were found to precede the increases in anti - hhv-6 igg levels in anticonvulsant hsr patients and were absent in controls . the presence of hhv-6 dna in pbmcs was found to correlate with the magnitude of anti - hhv-6 antibody titers ( p = 0.0002 ) . intermittent detection of hhv-6 dna in pbmcs was not indicative of illness , such that hhv-6 dna can be found in the pbmcs at low levels in immunocompetent children , with and without symptoms . significant increases in anti - hhv-6 igg titers were noted in all 6 patients included in a study . hhv-6 reactivation was observed between 17 and 27 days after the onset of the reaction . the presence of hhv-6 dna in plasma or serum is evidence of active hhv-6 infection . in addition , the presence of serum anti - hhv-6 igm and increases in the levels of anti - hhv-6 igg levels are used to differentiate primary hhv-6 infection ( i.e. , seroconversion ) from hhv-6 reactivation . serum anti - hhv-6 igg was detected in 7 dress patients analyzed , with serum anti - hhv-6 igm detected in only 4 ( 57.1% ) patients . seroconversion was diagnosed in 2 patients , in which serum anti - hhv-6 igm titers were initially undetectable and became detectable in subsequent serum samples , coinciding with increases in anti - hhv-6 igg titers . seroconversion is described in detail in a 56-year - old male patient with aromatic anticonvulsant - induced hsr . aside from the presentation of fever and cutaneous symptoms , other features of hhv-6 reactivation can include lymphadenopathy , hepatosplenomegaly , encephalitis caused by the virus , and severe lymphocytopenia . hhv-6 replication in hepatocytes led to severe hepatitis , associated with elevated enzyme levels , in an 18-year - old female . higher odds of detecting hhv-6 dna in pbmcs and liver biopsies were found in cases of fulminant hepatic failure or acute decompensation of chronic liver disease , compared to chronic liver disease ( p = 0.02 ) , in a sample of 23 children ( median age 24 months ) with acute liver failure . similarly , higher hhv-6 dna levels were found in cases of fulminant hepatic failure or acute decompensation of chronic liver disease , compared to chronic liver disease cases ( p = 0.0043 ) . tumor necrosis factor- ( tnf )  and interleukin- ( il ) 6 levels were initially elevated prior to hhv-6 reactivation in 4 ( 66.7% ) of 7 patients in a study . il-6 levels were once again elevated after hhv-6 infection in 5 ( 83.3% ) of 6 patients . il-6 and tnf- are produced primarily by monocytes and macrophages , the likely reservoir cells of latent hhv-6 . these cytokines likely play an important role in viral reactivation , yet the low number of patients analyzed in this study makes a definite answer impossible . serum levels of il-5 , interferon ( ifn)- , and eosinophil cationic protein were increased on day 29 and decreased on day 39 during an episode of carbamazepine dihs . an interesting case of drug sensitization was observed in a patient who developed symptoms of dihs within a few days of being exposed to the antibiotic cefaclor . this patient was previously exposed to cefaclor during an episode of carbamazepine - induced dihs . slight increases in il-5 , il-6 , il-10 , ifn- , and eosinophil cationic protein were elevated in sera on day 6 of cefaclor dihs . a drug - induced lymphocyte stimulation test using pbmcs showed that the patient was sensitized to carbamazepine during the first episode , but not to cefaclor . results of the test showed sensitivity to cefaclor during the second episode . during the first episode , carbamazepine - induced hsr was diagnosed 17 days after the start of carbamazepine , consistent with dihs . also , symptoms persisted after the drug was interrupted , and the patient responded to pulsed intravenous ( iv ) methylprednisolone . in contrast , the patient developed the symptoms much quicker during the second episode , during which time the symptoms were milder and disappeared faster after interruption of cefaclor . the involvement of hhv-6 during the first episode was established with anti - hhv-6 igg titers and hhv-6 dna . the magnitude of inflammatory cytokine increase was higher , and eosinophilia was more pronounced during the more severe carbamazepine - induced dihs , prompting aihara et al . to argue that hsr is mediated by both elevated inflammatory cytokine levels and activated eosinophils . it is also possible that corticosteroids administered as initial treatment for drug toxicity are involved in the reactivation of hhv-6 , epstein - barr virus ( ebv ) , and cytomegalovirus ( cmv ) , which became active in the later stage of the disease . anti - hhv-6 igg titers were elevated in 7 dihs patients 2138 days after the onset of the reaction . an elevation in anti - cmv igg was observed in all patients 3554 days after the onset of the reaction . only 2 patients experienced an elevation in anti - ebv igg , 37 and 48 days after the onset of the reaction . antibodies to herpes simplex virus , varicella - zoster virus , human parvovirus b19 , rubella , and measles were not changed . viral dna was detected in whole blood in all patients for whom anti - viral igg was observed , and in serum for 6 of 7 hhv-6 patients , 5 of 6 hhv-7 patients , and all cmv and ebv patients . there appears to be a correlation between relapse of symptoms and detection of increased viral loads for the virus that gets reactivated first ( i.e. , hhv-6 or hhv-7 ) . further immune system perturbations brought about by the initial hhv reactivation are believed to be triggers for subsequent reactivation of other hhvs . cihhv-6 was described and quantified in healthy blood donors and various hospital populations ( e.g. , organ transplant recipients and immunosuppressed patients ) [ 28 , 6167 ] . the mean viral loads in whole blood ranged from 10  copies / ml to 10  copies / ml [ 28 , 62 , 64 ] . vertical transmission of inherited chromosomal integration in addition , there are reports of cihhv-6 acquisition through bone marrow transplant , followed by the presence of hhv-6 in every cell derived from hematopoietic stem cells [ 24 , 6971 ] . it is not known if cihhv-6 can activate from its integrated state in vivo , but several lines of evidence suggest that this is a significant possibility . integrated hhv-6 has been shown to be activated in vitro   using histone deacetylase inhibitors and other compounds known to reactivate herpesviruses from latency . as previously discussed , transmission of cihhv-6 from infected mothers to their non - cihhv-6 infants , via the placenta , is another indicator that cihhv-6 may be activated from its integrated state in vivo . children suspected of encephalitis in the united kingdom had a four times greater rate of cihhv-6 than the general population , and liver transplant patients with cihhv-6 have higher rates of graft rejections and opportunistic infections . marek 's disease virus , a herpesvirus associated with tumors in chickens , can reactivate from its integrated state in vitro . if specific drugs can cause integrated virus to activate , then individuals with cihhv-6 may be at an increased risk for drug - induced hsr . report the case of a 47-year - old japanese male with fever ( 38.8c ) and generalized erythematous rash 78 days after carbamazepine exposure . mild hepatotoxicity ( alt 70  iu / l , ast 73  iu / l , -glutamyl transpeptidase 129  iu / l , and lactate dehydrogenase 686 u / l ) and hypogammaglobulinemia ( igg 609  mg / dl , iga 34  mg / dl and igm 27  mg / dl ) were measured . an abdominal skin biopsy revealed hydropic and vacuolar degeneration of epidermal basal cells , lymphocytic infiltration in the epidermis , and a dense upper dermal infiltrate consisting mainly of mononuclear cells . anti - hhv-6 igg titers were increased 128-fold 6 weeks after the reaction onset , while anti - hhv-6 igm titers remained unchanged throughout the course of the reaction , pointing towards hhv-6 reactivation . dna was persistently high in serum ( > 10000  copies / ml ) and whole blood . hhv-6 dna levels in primary infection and acute reactivation are typically below 5.5  10  copies . of interest , the only cases reported of viral loads above this level ( or in the same range as individuals with cihhv-6 ) appear to be those with graft - versus - host disease or dihs , two conditions that have very similar symptoms and courses [ 18 , 27 , 74 ] . in the present paper , we review cases of hsr associated with hhv-6 reactivation . in the vast majority of patients , hhv-6 infection occurs during infancy or early childhood . following resolution of the primary infection , the virus remains latent in salivary glands , pbmcs , and the central nervous system . reactivates in immunosuppressed individuals and is associated with fever , rash , encephalitis , bone marrow suppression , and transplanted organ rejection . primary hhv-6 infection can be identified by the presence of hhv-6 dna in the serum , plasma , or cerebrospinal fluid , or reverse transcription pcr in the absence of elevated antibody titers . reactivation is marked by detection of both viral dna and elevated anti - hhv-6 antibody titers . as anti - hhv-6 igg levels increase during the course of the reaction , anti - hhv-6 igm levels remain constant around < 1  :  20 in patients with hhv-6 reactivation [ 42 , 75 ] . hsrs seem to occur with almost a thousandfold higher incidence in aids patients compared to immunocompetent individuals exposed to the same medication , as there is a much higher exposure to drugs in these patients , as well as a much higher incidence of viral infections [ 76 , 77 ] . aside from a higher incidence of hsr , hiv positivity can also lead to more severe symptoms , compared to hiv - negative patients . in addition , an in vitro study showed increased dna viral replication in pbmcs belonging to dihs patients that were depleted for natural killer cells ( nk ) . these findings point toward an extensive immune barrier aimed against dihs development , while immune defects in components of these pathways can explain why only a relatively small amount of the population exposed to a drug will develop the reaction . suggest that hhv-6 reactivation is not a consequence , but rather a prerequisite for anticonvulsant hsr . the expansion of cd4 t cells and cd8 t cells in response to hhv-6 reactivation seems to be of extreme importance in the development of multiple organ failure during the course of anticonvulsant hsr . from their immunological findings , believe that continuous anticonvulsant therapy leads to transient immune dysfunction , marked by decreased igg production . while t cells protect against reactivation of viruses from a latent stage , antibodies prevent the dissemination of reactivating lytic virus . therefore , dihs may occur when transient drops in b cell counts and immunoglobulin production allow hhv-6 to be reactivated from latency , in conjunction with the presence of drug - specific t cells . the likely explanation for the lag between start of anticonvulsant therapy and onset of disease is that time is required for immunoglobulin levels to drop below a certain threshold . an in vitro study using the human t cell line mt4 found that therapeutic doses of both sodium valproate and carbamazepine led to enhanced hhv-6b replication in a dose - independent manner , whereas phenytoin and sulfasalazine had no effects on hhv-6b replication or cell proliferation . in vivo , there have been reports of phenytoin and sulfonamide antibiotics leading to hhv-6 reactivation in dihs patients [ 42 , 43 , 47 , 52 ] . as such , while widespread , hhv-6 infection is not encountered in all dihs cases . for example , hhv-6 dna was detected by pcr in blood or serum in a 25-year - old female treated with phenobarbital , while it was absent in a 21-year - old female treated with phenytoin . matsuda et al . describe 2 cases of carbamazepine - induced dihs in which no viral reactivation was observed . symptoms , including fever , skin eruptions , and liver involvement , occurred between 22 days and 4 weeks after carbamazepine initiation in the two patients , which is consistent with dihs . furthermore , eosinophilia and a drop in white blood cell count were observed in both patients . hhv-6 reactivation typically occurs 2 - 3 weeks after the development of rash in dihs patients [ 8 , 76 ] . hhv-6 reactivation is often accompanied by relapse of fever and hepatitis . a cascade of viral reactivation can then be started , with hhv-6 , ebv , and/or hhv-7 at the top , followed , with some delay , by other herpes viruses , particularly cmv . reactivation of these viruses is followed by development or exacerbation of clinical symptoms of dihs , including various organ failures [ 8 , 76 , 80 ] . of particular interest is cmv reactivation , which can be followed by transient fever , skin rash , myocarditis , pneumonia , or gastrointestinal bleeding . clinical symptoms ( fever , hepatitis , and/or skin rash ) correspond to the appearance of detectable hhv-6 dna levels . fever and/or hepatitis are the most common clinical features of hhv-6 reactivation in dihs patients . based on these findings , hhv-6 reactivation leads to a more severe course of disease in patients with dihs . hhv-6 reactivation is associated with more severe organ involvement and a prolonged course of the disease in patients with drug rash and systemic symptoms , compared with the remaining patients who did not experience hhv-6 reactivation . significant detection of hhv-6 dna corresponds to the presence of anti - hhv-6 igg titers , and there is a positive correlation between hhv-6 dna detection and the development of fever and hepatitis . while hhv-6 reactivation is a common feature of dihs / dress , hhv-6 dna was not detected in 15 patients with generalized morbilliform / maculopapular drug reactions . hhv-7 , cmv , or ebv dna was not detected in any of the patients included in this study . in situ hybridization revealed hhv-6 mrna in a small subset of infiltrating mononuclear cells around blood vessels and appendages in dihs patients only . similarly , only 1 ( 25.0% ) of 4 sjs / ten patients for whom data was available showed an increase in anti - hhv-6 igg titers from 1  :  10 to 1  :  1280 . aside from a lower likelihood of hhv-6 reactivation , sjs / ten is marked by a quicker onset of reaction than dihs / dress ( 2 - 3 weeks versus a mean 34 days ) . however , fever ( > 38.5c ) , leukocytosis , eosinophilia , and atypical lymphocytosis were common features of both sjs / ten and dihs / dress , whereas liver dysfunction was observed predominantly in sjs / ten patients and lymph node enlargement was observed predominantly in dihs / dress patients . treatments for sjs / ten included systemic corticosteroids in 7 ( 87.5% ) patients and iv immunoglobulin in 1 ( 12.5% ) patient . furthermore , teraki et al . warn that some of the clinical features of anticonvulsant - induced sjs / ten may differ from sjs / ten induced by other drugs , such as a more delayed onset of symptoms in the former category . additionally , the rate of hepatic dysfunction and hematological anomalies was also higher than that described with sjs / ten induced by other drugs . hhv-6 reactivation and atypical lymphocytosis were observed in dihs patients predominantly , compared to sjs / ten patients . the precise morphological nature of the skin reaction is another criterion used to differentiate dihs from sjs / ten . carbamazepine was associated with 12 ( 52.2% ) of 23 anticonvulsant hsr cases reported in a cohort study . maculopapular exanthematous eruptions were observed in 15 patients , erythroderma in 11 patients , exfoliative dermatitis in 3 patients , bullous eruption in 1 patients , urticaria in 1 patient , and purpura ( vasculitis ) in 2 patients . there was no relationship between the drug used and the length or severity of the reaction . in addition to the skin , 20 ( 87.0% ) patients had at least one other organ affected by the reaction , while 8 ( 34.8% ) patients had at least two other organs affected by the reaction . dili was observed in 12 ( 52.2% ) patients , and kidney involvement was observed in 8 ( 34.8% ) patients . other affected organs include the spleen ( splenomegaly ) , the lung , the thyroid ( hypothyroidism ) , the heart , and the pancreas . drug - drug interactions are particularly problematic when several pharmaceutical agents capable of inducting hsr are administered simultaneously . for example , conilleau et al . report the case of a child exposed intermittently to two anticonvulsants prior to developing dihs . despite ethosuximide being interrupted prior to hospitalization and sodium valproate being associated more often with dihs , it appears that the reaction was caused by the combination of these two structurally unrelated anticovulsants , as a patch test was positive for both ethosuximide and sodium valproate . in a separate case , an infant that was exposed to carbamazepine , phenytoin , and phenobarbital presented with initial hhv-6 infection . despite the patient being diagnosed with phenobarbital hypersensitivity , all three of these aromatic antiepileptic drugs have the potential to cause hsr . minocycline - induced dihs with ebv reactivation was reported in a 24-year - old african american female . sequential activation of hhv-6 , hhv-7 , herpes simplex virus , and cmv was observed in a 46-year - old male who developed dihs after being exposed to cyanamide , a drug used to control alcoholism . hhv-6 reactivation was observed in 2 elderly patients with allopurinol dihs [ 26 , 79 ] , and ebv reactivation was observed in a 40-year - old black male with allopurinol dihs and pancreatitis . the cause of the reaction was unknown in an 18-year - old female with sjs / ten exposed to valacyclovir , promethazine , synthroid , belladonna , and orthotricycline . in addition to anticonvulsants , patients can be exposed to additional medication for the treatment of comorbid diseases , opportunistic infections , or even for the management of hsr symptoms ( e.g. , antibiotics or nonsteroidal inflammatory drugs administered for the treatment of fever ) . furthermore , epilepsy patients are often exposed to more than one anticonvulsant , most of which are capable of causing an hsr . while medication is interrupted at the time of hsr diagnosis and the patient is encouraged to avoid rechallenge with the drug that was deemed to have initiated the reaction , it is still important that all medication is considered and tested individually for its capacity to initiate an hsr . investigators seldom check to see if there is an additive effect between the incriminated anticonvulsant and other medication , or if the anticonvulsant caused the reaction on its own . also , it is unlikely that hhv-6 reactivation is measured upon admission . as a result , it is difficult to establish whether the drug or the virus initiates the reaction . the same investigators report the case of a 46-year - old woman who developed dihs 4.5 months after initiating therapy with zonisamide and corticosteroids . since the reaction occurred well outside the time frame characteristic of dihs and since reactivation of herpes viruses was not measured , it is possible that this phenomenon could have created the conditions necessary for dihs to occur in this patient with long - term exposure to anticonvulsant therapy . the presence of proinflammatory cytokines during dili and scar is supported by findings that a significantly higher number of eosinophils was found both in the blood and tissue of patients with a drug - induced maculopapular exanthems , compared to control subjects with normal skin and skin from patients with psoriasis . the presence of hla - a*3101 allele and homozygosity for epoxide hydrolase 1 ( ephx1 ) single nucleotide polymorphism rs1051740 ( t - c ) in exon 3 , associated with modifications in epoxide hydrolase activity , were found in a patient with anticonvulsant hsr , possibly triggered by hhv reactivation , suggesting a genetic predisposition to hsr upon hhv reactivation . hhv-6 reactivation can be further observed in the absence of an hsr and is primarily associated with hepatotoxicity . phillips et al . were able to show with the help of transmission electron microscopy that full and empty virus capsids accumulate in the nucleus of hepatocytes , while viral particles bud out into the nuclear envelope and the cytoplasm . over the years , several drugs were used to treat hhv reactivations per se , as well as opportunistic infections in hsr patients with hhv reactivation , including idoxuridine , cytarabine , and vidarabine . vancomycin was used to treat an opportunistic infection with staphylococcus aureus in a dihs patient with hhv-6 reactivation . however , treatment against hhv-6 reactivation is often withheld out of fear of worsening the condition due to an increasing number of drugs that the patient is exposed to . drug - induced adverse reactions represent a concern for patients , clinicians , the pharmaceutical industry , and health providers . interestingly , very little mention of hhv-6 reactivation is made in a comprehensive article discussing dili , including acute liver failure in major dili registries from europe and the united states . in conclusion , this paper provides a multifaceted assessment of drugs implicated in hsr that have been reported to induce hhv-6 reactivation . this information may facilitate the possible link between the diagnosis of scar and dili , and hhv-6 reactivation .