Bugs and Drugs: What s New in Hypersensitivity Reactions? Erin Mathes, MD Associate Professor of Dermatology and Pediatrics University of California, San Francisco
DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY Erin Mathes, MD S006 - Treating Severe Skin Disease in Children 02/16/2018, 9:00 AM DISCLOSURES Zosano Pharma, Consultant, Honoraria Rodan + Fields, Advisory Board, Honoraria
Causes of SJS/TEN in Kids Retrospective study of kids with SJS/TEN at Sick Kids and Children s Hospital Boston between 2000-2007 55 cases: SJS 47, TEN 5, SJS/TEN 3 2% 18% 25% 20% 29% 9% Mycoplasma HSV Antiepileptics Antibiotics Chemotherapy Undetermined Finkelstein Y, et al. Pediatrics. Sept 2 2011
Mycoplasma Induced Rash and Mucositis Systematic Review Epidemiology Young (mean 11.9 years) Male (66%) Morphology Mucosal predominant Mild skin involvement Outcomes Pigmentary alteration 6% Mucosal complications 8% Recurrence in 8% Mortality 3% (all in 1940s pre-antibiotics) Canavan T, et al. J Am Acad Dermatol 2015;72:239-45.
Outbreak of Mp-Associated SJS Outbreak of SJS at Children s Hospital Colorado Mp associated SJS cases significantly more likely to have Pneumonia Preceding respiratory sx ESR 35 3 affected skin sites ( severity of skin was overall mild ) Treatments and length of stay were similar (mucosal dz was severe). Olson D, et al. Pediatrics 2015; 136: e386-394.
MIRM Diagnostic Criteria <10% BSA detachment* 2 mucosal sites Few atypical targets Evidence of atypical pneumonia (clinical and laboratory) *Rare cases can have more BSA detachment, or no rash. + Age Criteria (3-18yrs?, 5-21yrs?) Canavan T, et al. J Am Acad Dermatol 2015;72:239-45. Canavan T, et al. J Am Acad Dermatol 2015 Aug;73(2):e69.
IgM/IgG IgA? How good are our tests for Mycoplasma pneumoniae? Specificity 25-100% Sensitivity 52-100% Titers rise earlier than IgM. PCR respiratory (nasal wash or BAL), bulla fluid, skin bx Very sensitive Can shed bacteria for 4 months in OP Not easily available at all hospitals VukicI, et al. JEADV 2015, 29, 595 598. Waris et al, 1998, J Clin Microbio
Mycoplasma + Skin Skin findings in up to 33% of Mp infections Wide range of cutaneous findings Exanthema (8-33% of Mp infections) Erythema nodosum Urticaria Stevens Johnson syndrome (1-5% of Mp infections) Schalock PC et al. Int J Dermatol. 2009 Jul;48(7):673-80
On your DDx: CIRM Chlamydia pneumoniae induced rash and mucositis 21 cases of mucositis/rash associated with CP reported Very similar to MIRM Young, preceding URI Dx with PCR or Ig s Treat with azithromycin Pediatr Dermatol. 2017 Jun 1. PubMed PMID: 28568680.
Pediatric Work-Up Mycoplasma IgM, IgG, IgA Mycoplasma PCR HSV IgM, IgG CXR Drug Chart Skin Biopsy H&E, DIF Consider: Viral PCRs IIF ESR Others based on ddx
MIRM: Treatment Treat pulmonary infection with azithromycin Supportive care Other interventions: Steroids? after infection treated à shorter LOS? Cyclosporine? IVIG? Rarely. If skin progresses to >10% BSA. Amniotic membrane for eyes if severe. Olson D, et al. Pediatrics 2015; 136: e386-394. Ahluwalia J, et al. Pediatr Dermatol. 2014 Nov-Dec;31(6):664-9.
SJS/TEN Medication Triggers Antiepileptics Phenobarbital Carbamazepine Lamotrigine Valproic acid Antibiotics Sulfonamides NSAIDS Paracetamol/Acetominophen Levi N, et al. Pediatrics 2009;123:e297 e304 Finkelstein Y, et al. Pediatrics. Sept 2 2011
Steroids Meta-analysis and individual patient data analysis of 3248 patients Statistically significant benefit of corticosteroids in 1 of 3 analyses. Zimmerman S, et al. JAMA Dermatol. 2017;153(6):514-522.
Steroids? In children with SJS do systemic steroids reduce morbidity or mortality? Few quality studies Steroids may Shorten fever duration & increase complication rate Occasionally use in SJS with evidence of ongoing inflammation Use 1-2mg/kg/day x ~5 days Caution in kids with behavioral or psych diagnoses J Popul Ther Clin Pharmacol Vol 18(1):e121-e133; 2011 Corrick & Anand. Arch Dis Child 2013; 98:828-830.
IVIG? IVIG cannot be recommended for SJS/TEN Zimmerman S, et al. JAMA Dermatol. 2017;153(6):514-522. Huang et al. BJD. 2012. 167; 424-432.
IVIG treated group: Children vs. Adults Children treated with IVIG do better than adults treated with IVIG. Huang et al. BJD. 2012. 167; 424-432.
Our approach to IVIG Use it in TEN and SJS/TEN overlap Use high dose 4 g/kg total (1 g/kg/day x 4 days) Occasionally use in combination with steroids *Children have lower risk of side effects from IVIG (thromboembolic and renal)
Cyclosporine Predicted mortality vs. observed mortality 4 studies (few children) 2 retrospective 2 prospective open Different CSA protocols 3mg/k x 7 days 3, 2, 1 mg/k x 10 d each Reduction in observed deaths compared with deaths predicted by SCORTEN Kirchoff M, et al. JAAD. 2014 Jul 30. Singh GK, et al. Indian J Dermatol Venereol, 79 (2013). Valeyrie-Allanore, L et al. Br J Dermatol, 163 (2010) Lee HY, et al. J Am Acad Dermatol. 2017 Jan;76(1):106-113
CSA: Pediatric Data 3 children treated with CSA for MIRM, SJS, SJS/TEN Dose 3mg/kg/day div BID (x 7-21 days) Time to response 2.2 days (1.5-3 days) Well tolerated St John J, et al.2017 Sep;34(5):540-546
Outcomes of SJS/TEN Spectrum Mortality is very low in children (0.3-1.5%)* More meaningful outcome measures: Complications Time to remission Length of hospital stay (7-9 days)* Scarring (ocular, genital, oral, cutaneous) *Okubo Y, et al. Pediatr Dermatol. 2016 Dec 19. doi: 10.1111/pde.13050.
SJS Spectrum: Recurrence Pediatrics 2011-18% recurrence (children only) Not always the same trigger MIRM JAAD 2014 8% recurrence JAMA 2014-7% recurrence risk Higher risk if: younger, male, rural, academic hospital Finkelstein Y, et al. Pediatrics. 2011; 128:723 728 Finkelstein Y, et al. JAMA. 2014;311(21):2231-2232 Sokumbi O, et al. Int J Dermatol. 2012, 51, 889 902
Recurrent SJS/TEN Genetic predisposition likely Important part of our patients health history Life threatening allergy Risk of another similar reaction (not necessarily to a related trigger) Finkelstein Y, et al. Pediatrics. 2011; 128:723 728 Hirsch L, et al. Epilepsia. 2006; 47(2):318-322
11 yo girl w/sore throat, malaise, low grade fever, lymphadenopathy and a rash for 3 days. Taking minocycline for the last 4 weeks for periorificial dermatitis. LFTs are elevated.
Does she have a drug reaction or a viral syndrome?
Does she have a drug reaction or a viral syndrome? Both
DIHS = Drug induced hypersensitivity syndrome = DRESS = Drug Reaction with Eosinophilia and Systemic Signs
DIHS/DRESS Carroll M et al. Pediatrics 2001;108:485-92 Polymorphic rash, facial edema, LAD Systemic symptoms (pharyngitis, fever) Abnormal labs: éeos (40%), LFTs (80%), Cr (40%) Meds: Anticonvulsants Antibiotics Sulfonamides Allopurinol Abnormal drug metabolism (HLA associations) Starts 1-6 weeks after drug initiation
Role of Viruses in DIHS Viral reactivation (HHV-6, EBV, HHV-7, CMV): 30-80% patients Viral reactivation and visceral infection are associated with DRESS Viral antibody titers and viral load correlate with severity, duration Viral studies do not become positive immediately, can rise over weeks Check HHV-6, HHV-7, EBV, CMV antibody titers and viral loads weekly Chow ML, et al. Pediatr Dermatol. 2018;00:1 3. Ishida T, et al. Allergy. 2014;69:798-805.
Does virus type correlate with morphology? Restrospective study of Japanese patients (N=62) with DIHS, SJS, SJS/TEN, TEN Followed viral studies over 2 years DIHS HHV-6 elevated in acute phase SJS EBV in acute phase and after resoultion
DIHS Treatment must d/c med list med as an allergy systemic steroids for weeks to months start at 1-2 mg/kg/day additional immunosuppression if unable to taper steroids follow labs carefully as you taper Antiviral therapy may be helpful in addition to corticosteroids Gancyclovir HHV-6 and CMV Chow ML, et al. Pediatr Dermatol. 2018;00:1 3. Ishida T, et al. Allergy. 2014;69:798-805.
Is this child allergic to amoxicillin?
Aminopenicillin + EBV = Rash? Old studies: 69-100% got rash RR of rash = 5.5-11 à Not a true allergy, reversible New studies: 13-30% got rash RR of rash = 0.58-1 à Unclear if allergy or not. Arch Dis Child. 2016 May;101(5):500-2
Allergy vs. transient immunostimulation? Patients with confirmed EBV infection + rash when given amoxicillin Tested for allergy with specific IgE, prick tests, patch tests 5 of 8 had positive Amox patch tests, 1 positive oral challenge, 4 refused challenge 2 also positive patch to PCN all negative for Cephalosporins Jappe U. Allergy. 2007 Dec;62(12):1474-5
Amox rash bottom line Most common with EBV, but other viruses implicated Likely 2 populations: 1. Transient EBV associated loss of immune tolerance (most people) 2. True, peristent delayed-type hypersensitivity. Consider testing/referring to allergy (but know that the tests aren t perfect)
Bugs and Drugs Drugs and infections interact with the immune system and the skin in fascinating and complex ways. MIRM - distinct morphology, epidemiology SJS/TEN kids do better, consider CSA Complex drug reactions - look for viral infections
Thank you erin.mathes@ucsf.edu