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Drug Hypersensitivity with Eosinophilia and Systemic Symptoms

Drug Hypersensitivity with Eosinophilia and Systemic Symptoms. Mariana Castells, M.D., Ph.D. Presentation outline. Case presentation Hospital course Diagnosis Pathophysiology Dysfunction in drug metabolism Viral reactivation Treatment Corticosteroids N- acetylcysteine IVIG

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Drug Hypersensitivity with Eosinophilia and Systemic Symptoms

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  1. Drug Hypersensitivity with Eosinophilia and Systemic Symptoms Mariana Castells, M.D., Ph.D.

  2. Presentation outline • Case presentation • Hospital course • Diagnosis • Pathophysiology • Dysfunction in drug metabolism • Viral reactivation • Treatment • Corticosteroids • N-acetylcysteine • IVIG • Cyclosporine • Interferon • Desensitization • References

  3. 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: • Vancomycin • Aspirin • Captopril

  4. Adverse Cutaneous ReactionsBachot 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)

  5. Adapted from Cacoub et al “The DRESS Syndrome” The American Journal of Medicine, vol 124, no. 7, July 2011

  6. 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, 609-611

  7. 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

  8. Pathophysiology (cont.) • Verneuil et al, “Endothelial Damage in All Types of T-Lymphocyte-Mediated Drug-Induced Eruptions” Arch. Dermatol. 2011; 147 (5): 579-584(6): • Endothelial apoptosis in skin microvessels in all patients • 32 patients (8 SJS/TEN, 8 DRESS, 8 AGEP, 8 drug induced morbilliform exanthema)

  9. 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

  10. 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)

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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)

  16. 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 (?)

  17. 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

  18. 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

  19. References • Cacoub et al “The DRESS Syndrome” The American Journal of Medicine, vol 124, no. 7, July 2011 • 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 • 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 • Milliken et al, “Drug fever and DRESS syndrome” British Journal of Hospital Medicine 2011, vol 72, no. 4 • Tas et al, “Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update” Dermatology 2003; 206 (4): 353-356 • Verneuil et al, “Endothelial Damage in All Types of T-Lymphocyte-Mediated Drug-Induced Eruptions” Arch. Dermatol. 2011; 147 (5): 579-584 • 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

  20. References (cont.) • Sullivan et al, “The Drug Hypersensitivity Syndrome: What is the Pathogenesis” Arch Dermatol; 2001vol. 137 (357-363) • Aihara et al, “Pharmacogenetics of cutaneous adverse drug reactions” Journal of Dermatology 2011; 38: 246-254 • Picard et al, “Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): a Multiorgan Antiviral T Cell Response” Sci Transl Med; 2010; 2 (46-66) • 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. • 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 • 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 • Chen et al “Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases.” Arch Dermatol 2010 Dec;146(12):1373-1379 • 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

  21. References • Zuliani et at, “Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment” Clin Nephrol. 2005; 64 (2); 155-158 • Harman “Persistent anticonvultant hypersensitivity syndrome responding to ciclosporin.” Clin Exp Dermatol 2003; 28: 364–5. . • 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 • 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 • Cumbo-Nacheli et al, “Anticonvulsant hypersensitivity syndrome: is there a role for immunomodulation?” Epilepsia. 2008; 49(12):2108-12. • Kano et al “Association Between Anticonvulsant Hypersensitivity Syndrome and Human Herpesvirus 6 Reactivation and Hypogammaglobulinemia” Arch Dermatol. 2004; vol 140, 183-188

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