drug eruptions are common , affecting 23% of all hospitalized patients , and complications associated with medications make up the largest proportion of adverse events seen in hospitals .
drug eruptions can be difficult to diagnose , particularly causality , as even biopsies are nonspecific and patients are often on more than one potentially offending medication .
we present 3 cases that highlight these difficulties and the broad spectrum of drug eruptions in the setting of lymphoma patients receiving multidrug regimens including bendamustine .
a 60-year - old caucasian female presented with a 6-month history of constitutional symptoms , dyspnea on exertion , lymphadenopathy and pleural effusions and was diagnosed with stage iv marginal zone lymphoma with bone marrow involvement .
four to six weeks prior to admission , she had developed a progressive generalized erythematous rash and edema involving her trunk and extremities .
these findings were characterized as consistent with drug eruption , although no new drugs were identified in her history .
the decision was made to treat with bendamustine and rituxan as an inpatient due to nonresolving malignant pleural effusion .
her initial rash on presentation was thought to be due to possible lymphomatous involvement and lymphedema as it improved over the 23 days following chemotherapy . on day 7
she developed a bullous rash involving 6070% of her skin as well as mucosa ( fig .
a new biopsy revealed vacuolar interface dermatitis with necrosis of keratinocytes in the epidermis , with the underlying dermis displaying a superficial perivascular lymphocytic inflammatory infiltrate with eosinophils ( fig . 2 ; fig .
3 ) . she began to deteriorate rapidly with a clinical course further complicated by the development of severe hepatic and renal failure .
a diagnosis of dress syndrome was made . despite a high dose of steroids , the rash spread , eventually involving 100% of her body surface area , including her eyelids , conjunctiva , oral and vaginal mucus membranes . despite the use of filgrastim and broad spectrum antibiotics
the second case was a 66-year - old male diagnosed in 2009 with chronic lymphocytic leukemia associated with the deletion of chromosome 13 . in 2012 , his lymphocyte count reached 253,000 , and he developed autoimmune hemolytic anemia .
he initially received one cycle of intravenous immunoglobulin , cyclophosphamide , vincristine and prednisone ( without rituxan ) .
the initial cycle was again given without rituxan due to the high burden of the disease .
he received antibiotic therapy with cefepime , fluconazole , azithromycin and levofloxacin during two separate hospitalizations .
two days following the second admission ( day 7 following bendamustine ) , he developed a generalized erythematous rash with desquamation that did not resolve with the discontinuation of cefepime or the administration of rituxan .
his rash slowly resolved . a second episode of nonneutropenic fever , hypotension and acute renal failure occurred with the second cycle of bendamustine and rituxan 2 months later .
this resolved as well . given the timing of the reaction , it was questioned that the offending drug was bendamustine in both events .
the third patient was a 59-year - old female diagnosed with stage ivb splenic marginal zone lymphoma after presenting with constitutional symptoms and urticaria .
she was treated with splenectomy and systemic chemotherapy consisting of bendamustine and rituxan . prior to the third cycle ,
the eruption worsened 2 weeks later as the lesions became intensely pruritic , erythematous and ulcerative . despite the treatment with antibiotics and corticosteroids , she progressed over the course of 1 week to a tense bullous rash covering the extremities .
a 60-year - old caucasian female presented with a 6-month history of constitutional symptoms , dyspnea on exertion , lymphadenopathy and pleural effusions and was diagnosed with stage iv marginal zone lymphoma with bone marrow involvement .
four to six weeks prior to admission , she had developed a progressive generalized erythematous rash and edema involving her trunk and extremities .
these findings were characterized as consistent with drug eruption , although no new drugs were identified in her history .
the decision was made to treat with bendamustine and rituxan as an inpatient due to nonresolving malignant pleural effusion .
her initial rash on presentation was thought to be due to possible lymphomatous involvement and lymphedema as it improved over the 23 days following chemotherapy . on day 7
she developed a bullous rash involving 6070% of her skin as well as mucosa ( fig .
a new biopsy revealed vacuolar interface dermatitis with necrosis of keratinocytes in the epidermis , with the underlying dermis displaying a superficial perivascular lymphocytic inflammatory infiltrate with eosinophils ( fig . 2 ; fig .
3 ) . she began to deteriorate rapidly with a clinical course further complicated by the development of severe hepatic and renal failure .
a diagnosis of dress syndrome was made . despite a high dose of steroids , the rash spread , eventually involving 100% of her body surface area , including her eyelids , conjunctiva , oral and vaginal mucus membranes . despite the use of filgrastim and broad spectrum antibiotics
the second case was a 66-year - old male diagnosed in 2009 with chronic lymphocytic leukemia associated with the deletion of chromosome 13 . in 2012 , his lymphocyte count reached 253,000 , and he developed autoimmune hemolytic anemia .
he initially received one cycle of intravenous immunoglobulin , cyclophosphamide , vincristine and prednisone ( without rituxan ) .
the initial cycle was again given without rituxan due to the high burden of the disease .
he received antibiotic therapy with cefepime , fluconazole , azithromycin and levofloxacin during two separate hospitalizations .
two days following the second admission ( day 7 following bendamustine ) , he developed a generalized erythematous rash with desquamation that did not resolve with the discontinuation of cefepime or the administration of rituxan .
his rash slowly resolved . a second episode of nonneutropenic fever , hypotension and acute renal failure occurred with the second cycle of bendamustine and rituxan 2 months later .
this resolved as well . given the timing of the reaction , it was questioned that the offending drug was bendamustine in both events .
the third patient was a 59-year - old female diagnosed with stage ivb splenic marginal zone lymphoma after presenting with constitutional symptoms and urticaria .
prior to the third cycle , the patient developed a mild pruritic eruption with raised plaques .
the eruption worsened 2 weeks later as the lesions became intensely pruritic , erythematous and ulcerative . despite the treatment with antibiotics and corticosteroids , she progressed over the course of 1 week to a tense bullous rash covering the extremities .
severe drug eruptions associated with high morbidity and mortality include stevens - johnson syndrome and toxic epidermal necrolysis .
these syndromes are often confused and may represent a continuum of each other , with toxic epidermal necrolysis having > 30% of epidermal detachment and stevens - johnson syndrome having only 10% or less
morbidity and mortality from these conditions stem from their complications including massive fluid losses , electrolyte imbalances , infections and diffuse interstitial pneumonitis , leading to acute respiratory distress syndrome .
dress syndrome represents another severe drug eruption with a 10% mortality rate , typically in the setting of hepatic failure .
the term dress syndrome was later coined in 1996 as a syndrome specifically describing a drug eruption with internal organ involvement and hematologic abnormalities , particularly eosinophilia or atypical lymphocytosis .
dress syndrome can be difficult to diagnose , as onset is typically 26 weeks after the drug was administered but is more probable when associated with hypereosinophilia , liver involvement , fever and lymphadenopathy .
etiology , as with other severe drug eruptions , is unclear but postulated to be associated with human herpes virus reactivation .
many drugs have been implicated in dress syndrome ; however , the ones most often reported are allopurinol , penicillins , sulfonamides and antipsychotics .
severity and likelihood of the diagnosis of dress as well as other severe cutaneous drug reactions are scored using the regiscar in europe .
the mainstay of treatment remains the removal of the offending drug and supportive care with the use of steroids remaining controversial in their effectiveness [ 2 , 5 ] .
bendamustine was first synthesized in 1963 as a chemotherapeutic agent with both antimetabolite and alkylating properties .
since that time , bendamustine has demonstrated significant efficacy in many lymphoma subtypes , particularly indolent lymphomas resistant to other alkylators . in 2008 ,
it was approved by the fda for the treatment of rituximab - refractory chronic lymphocytic leukemia and indolent b - cell non - hodgkin lymphomas .
its side effect profile has been shown to be well tolerated , with the most common side effects being cytopenias and fatigue .
the fda prescribing guidelines state that skin reactions have been reported with bendamustine , most often in combination with another agent ( rituximab or allopurinol ) , so that true causality can not be determined .
however , these reactions have been reported to be severe and progressive with several deaths mentioned .
most described rashes develop following the first administration of bendamustine and generally worsen in severity over the following days .
one patient with b - cell prolymphocytic leukemia developed rash with palpable purpura and hemorrhagic plaques while thrombocytopenic .
this rash was preceded by a severe generalized maculopapular rash with most bendamustine skin reactions .
a biopsy revealed a diffuse eosinophilic infiltrate . in a case series of 16 patients with chronic lymphocytic leukemia or follicular lymphoma , over 50% of the patients developed an erythematous maculopapular rash .
another case report described a severe desquamating rash involving > 75% of the skin as well as oral mucosa .
a biopsy revealed interface dermatitis with a lymphohistiocytic infiltrate . in our case of dress syndrome ,
this led to the question of the offending agent ; however , the patient did not have a reasonable alternate medication exposure .
we also postulate that both the patient 's lymphoma and bendamustine itself may have induced a quicker response based on already reduced immunoglobulin levels and a rapid reduction in b - cell lymphocytes .
this initiating factor in the mechanism of dress was proposed by criado et al .   and has been cited as the reason for the long latency in cases .
case 2 represents the typical scenario of a drug exanthem where the causative agent is in question .
rash developed following bendamustine , but the patient was also exposed to antibiotics that are known to cause dermatologic complications .
however , unlike most reported cases , rituximab was not a questionable cause , as it was not administered with the bendamustine initially .
case 3 also represents a more atypical presentation than initially reported , with a reaction after the second cycle rather than after initial exposure to the drug . however , no other causative agent was found .
 cutaneous drug reactions make up the largest proportion of adverse events in the medical field . 
 causality , in particular , is difficult to determine , and therefore , preventing recurrent reactions can be challenging . 
 bendamustine was initially thought to be a well - tolerated chemotherapy agent with few side effects aside from bone marrow suppression . 
 however , the incidence of cutaneous reactions reported is rising . 
 we describe three such reactions in relation to bendamustine administration in hopes of adding to the awareness of such side effects . 
Introduction
Case Presentations
Case 1: Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome
Case 2: Stevens-Johnson Syndrome
Case 3: Bullous Pemphigoid
Discussion