Transcript Cancun WAO DRESS 2011

Drug Hypersensitivity with
Eosinophilia and Systemic
Symptoms
Mariana Castells, M.D., Ph.D.
Presentation outline
I.
Case presentation
A. Hospital course
B. Diagnosis
II.
Pathophysiology
A. Dysfunction in drug metabolism
B. Viral reactivation
III. Treatment
A.
B.
C.
D.
E.
F.
Corticosteroids
N-acetylcysteine
IVIG
Cyclosporine
Interferon
Desensitization
IV. References
Case presentation

Reason for consultation:
Fever, rash, eosinophilia, concern for drug-induced hypersensitivity
HPI:

44yo man with dm1, hyperlipidemia, admitted on 7/18/2011 with large anterior
STEMI.

Complicated clinical course, including dependence on pressors and inotropics,
and prolonged mechanical ventilation requiring tracheostomy.

Developed a rash on 8/16/2011 while at an outside hospital.
 Suspected medications:
1.
Vancomycin
2.
Aspirin
3.
Captopril
Adverse Cutaneous Reactions
Bachot and Roujeau 2003
 2-3 % of hospitalized patients, 8% general pop
 Morbiliform exanthem /maculopapular : 48-95%
 Urticaria/Angiodema 5-22%
 Severe reactions: 2-17%
Erythema Multiforme (EM)
Stevens-Johnson Syndrome (SJS)
Toxic Epidermal Necrolysis (TEN)
Hypersensitivity Syndrome/Drug Rash
with Eosinophilia and Systemic Symptoms (DRESS)
Acute generalized Exanthematous pustulosis (AGEP)
Adapted from Cacoub et al “The DRESS Syndrome” The American Journal of Medicine, vol 124, no. 7, July 2011
Adapted from Kardaun et al “Variability in the clinical pattern of cutaneous side-effects of drugs with
systemic symtoms: does a DRESS syndrome really exist?” British Journal of Dermatology 2007 156, 609611
Pathophysiology
 Potentially life-threatening severe skin eruption, with fever,
hematologic abnormalities, and internal organ involvement.
 Extremely heterogeneous
 Special susceptibility
 Common medications, infrequent reactions
 Associated with HLA-A*3101 in some Japanese patients9 , no
other strong pharmacogenetic studies
Pathophysiology (cont.)
 Verneuil et al, “Endothelial Damage in All Types of T-LymphocyteMediated Drug-Induced Eruptions” Arch. Dermatol. 2011; 147 (5): 579584(6):
 Endothelial apoptosis in skin microvessels in all patients
 32 patients (8 SJS/TEN, 8 DRESS, 8 AGEP, 8 drug induced morbilliform exanthema)
Pathophysiology (cont.)
 Dysfunction in drug metabolism and detoxification
 slow acetylation, reactive metabolite formation
 Generation of drug-specific T-cell recognition
 related with reactivation of human herpesviruses1,5, 8
 Prophylactic drug desensitization, decreased incidence if anticonvulsant is started
along with other anticonvulsants
 Dynamic Th1 (blistering disease, thyroiditis)/ Th2 (eosinophilic organ infiltration)
cytokine profile throughout disease course
 Choquet-Kastylevsky et al, “Increased levels of IL-5 are associated with the
generation of eosinophilia in drug-induced hypersensitivity syndrome” British
Journal of Dermatology 1998; 139: 1026-1032
 IL5 is typically elevated in DRESS when there is eosinophilia
 Some patients had DRESS and not eosinophilia (2/7)
 IL3 and GM-CSF were not elevated
 ELISA’s on: 7 patients with DRESS (DIHS), 8 drug exanthemas w/o eosinophilia, 5
patients w eosinophilia of other causes (IL5 was elevated but not as high as in
DRESS patients)
Pathophysiology (cont.)
 Picard et al, “Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS): a Multiorgan Antiviral T Cell Response” Sci Transl Med; 2010;
2 (46-66)
 40 patients with DRESS, 40 healthy individuals
 T lymphocytes were isolated and analyzed.
 Phenotype, cytokine secretion, CD4/CD8+ balance
 Excessive numbers of activated CD8+ with cutaneous homing marker (CLA)
 Antigenic sequences specific for EBV (+ cellular stimulation assay with EBV
peptides)
 Increased TNF-alpha, INF-gamma, IL2. IL5 was not increased.
Pathophysiology (cont.)
 In vitro studies showing some cases of increased viral
replication when DRESS patients are exposed to amoxicillin,
and valproate11
 “cannot be solely explained by drug antigen-driven oligoclonal
expansion of T cells: they include paradoxical worsening of
clinical symptoms after discontinuation of the causative
drug”12
 The long latency period in DHS/DRESS could be related to
the time delay in viral reactivation; the clinical variation to the
sequential nature of reactivation.3
 Viral reactivation in DRESS is similar to that seen in GVHD13
 Transient hypogammaglobulinemia 21
Treatment
 Drug discontinuation
 No RCT’s !
 Steroids
 Only if clinical worsening after discontinuation of offending
drug
 Chen et al “Drug reaction with eosinophilia and systemic
symptoms: a retrospective study of 60 cases.” Arch Dermatol
2010 Dec;146(12):1373-9
 75% tx’d with different regimens of steroids
 No difference in mortality between the 2 groups
 2 groups were vastly dissimilar
Treatment (cont.)
 Natkunarajah et al, “Ten cases of drug reaction with eosinophilia and
systemic symptoms (DRESS) treated with pulsed intravenous
methylprednisolone” European Journal of Dermatology; 2010. vol 21,
no. 3; pp 385-91
 10 patients:
 1 died 4 mo’s later of liver failure even after attempted liver tx
 1 lost to f/u
 Adverse events:1 of 8 that had long term f/u had persistent pruritus. 1 case of
steroid induced psychosis, 1 dm1.
 Many case reports
 Concern with relapse after tapering
Treatment (cont.)
 Cyclosporine
 When steroids fail
 2 case reports16, 17
 One in which a five day couse of cyclosporine resulted in
resolution of symptoms, in vancomycin-induced DRESS refractory
to steroids
 Another in which cyclosporine 4mg/kg/day was added after 1 yr on
prednisone and persistent symptoms (alopecia, erythroderma,
eosinophilic pneumonia)

Treatment (cont.)
 N-acetylcysteine
 Theoretical benefit
 Case reports3, 18-20
 Not recommended in the absence of RCT’s
 1 case report the patient died (also had brucellosis, and anca+
vasculitis)
 1 case report it was given at in dosing similar to acetaminophen
overdose. Was also given with IVIG, given after 5 days of iv
steroids not leading to any improvement.
 SE: 1 case report of angioedema secondary to NAC (?)
Treatment (cont.)
 IVIG
 3 case reports
 Interferon alpha
 No case reports
 Theoretical
 Desensitization
 Has been done in HIV~ drug exanthems that have a
theoretically similar pathogenesis
 Rash to lamotrigine, then rechallenged
 Not done in DRESS

Summary
 Complex, poorly understood, difficult to diagnose disease
 Susceptible individuals, altered drug metabolism,
associated with virus reactivation, varying cytokine profile
 Tx: varies by case
 Prednisone if clinically deteriorating
 ?NAC, IVIG, cyclosporine, interferon
References
1.
Cacoub et al “The DRESS Syndrome” The American Journal of Medicine, vol 124, no. 7, July 2011
2.
Kardaun et al “Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symtoms:
does a DRESS syndrome really exist?” British Journal of Dermatology 2007 156, 609-611
3.
Walsh et al “Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and
review of current thinking” Clinical and Experimental Dermatology 2010. 36, 6-11
4.
Milliken et al, “Drug fever and DRESS syndrome” British Journal of Hospital Medicine 2011, vol 72, no. 4
5.
Tas et al, “Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an
update” Dermatology 2003; 206 (4): 353-356
6.
Verneuil et al, “Endothelial Damage in All Types of T-Lymphocyte-Mediated Drug-Induced Eruptions”
Arch. Dermatol. 2011; 147 (5): 579-584
7.
Choquet-Kastylevsky et al, “Increased levels of IL-5 are associated with the generation of eosinophilia in
drug-induced hypersensitivity syndrome” British Journal of Dermatology 1998; 139: 1026-1032
References (cont.)
8.
Sullivan et al, “The Drug Hypersensitivity Syndrome: What is the Pathogenesis” Arch Dermatol; 2001vol. 137 (357-363)
9.
Aihara et al, “Pharmacogenetics of cutaneous adverse drug reactions” Journal of Dermatology 2011; 38: 246-254
10.
Picard et al, “Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): a Multiorgan Antiviral T Cell Response” Sci
Transl Med; 2010; 2 (46-66)
11.
Mardivirin et al, “Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms:
report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus replication in vitro” Eur J
Dermatol 2010; 20 (1): 68-73.
12.
Shiohara et al “Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses
and antiviral and antidrug immune responses” Allergol Int 2006 Mar;55(1):1-8
13.
Kano et al “Several herpesviruses can reactivate in a severe drug-induced multiorgan reaction in the same sequential order as in
graft-versus host disease” British Journal of Dermatology 2006; 155, pp301-306
14.
Chen et al “Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases.” Arch Dermatol 2010
Dec;146(12):1373-1379
15.
Natkunarajah et al, “Ten cases of drug reaction with eosinophilia and systemic symptoms (DRESS) treated with pulsed
intravenous methylprednisolone” European Journal of Dermatology; 2010. vol 21, no. 3; pp 385-91
References
16. Zuliani et at, “Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following
cyclosporine treatment” Clin Nephrol. 2005; 64 (2); 155-158
17. Harman “Persistent anticonvultant hypersensitivity syndrome responding to ciclosporin.” Clin Exp Dermatol
2003; 28: 364–5. .
18. Albayrak et al, “DRESS syndrome with fatal results induced by sodium valproate in a patient with
brucellosis and a positive cytoplasmic antineutrophilic cytoplasmic antibody test result.” Rheumatol Int
2010, Mar 31
19. Simonart et al “Hazards of therapy with high doses of N-acetylcysteine for anticonvulsant-induced
hypersensitivity syndrome” British Journal of Dermatology. 1998; 138 (3) 553
20. Cumbo-Nacheli et al, “Anticonvulsant hypersensitivity syndrome: is there a role for immunomodulation?”
Epilepsia. 2008; 49(12):2108-12.
21. Kano et al “Association Between Anticonvulsant Hypersensitivity Syndrome and Human Herpesvirus 6
Reactivation and Hypogammaglobulinemia” Arch Dermatol. 2004; vol 140, 183-188