An Evidenced-Based Approach to the Adult with a Morbilliform Eruption

Transcription

1 Relatively An Evidenced-Based Approach to the Adult with a Morbilliform Eruption Ben Kaffenberger, MD Assistant Professor, Dermatology Director, Inpatient Dermatology Consult Service Ohio State University Wexner Medical Center

2 Disclosures: Conflicts of Interest: Investigator: Celgene, Biogen, Xbiotech, Eli Lilly Co. Grant Funding: Ohio Dept. of Medicaid, SPARC Awards (NIH + Takeda Pharma + Eli Lilly Co.), National Rosacea Society, American Acne and Rosacea Society My Wife s Conflicts of Interest: Janssen, Novartis, Amgen, Sandoz, Abbvie, Eli Lilly Co. Off Label Treatments: Yes

3 . Items to Discuss: 1. Drug and Contrast Eruptions 2. Differentiating Low Risk from High Risk Reactions 3. Viral Eruptions Eruptions NOT included 1. Toxic Erythema of Chemotherapy 2. Acute GVHD vs eruption of lymphocyte recovery vs engraftment syndrome

4 How often do morbilliform eruptions occur as a percentage of all drug reactions? Patel et al. Indian J Dermatol Venereol

5 How often do morbilliform eruptions occur as a percentage of all drug reactions? Table 2. Adverse cutaneous drug reactions in hospitalized patients Dermatologic diagnoses % Morbilliform exanthema 51.2 Urticaria 12.2 Erythema multiforme 4.9 Acute generalized exanthematous pustulosis 2.4 Fixed drug eruption 2.4 Acneiform dermatitis 2.4 Erythroderma (1 intrahospital 2.45%) 4.9 Erythema multiforme on admission 2.4 Stevens Johnson syndrome 4.9 Toxic epidermic necrolysis and 2.4 Carbamazepine hypersensitivity syndrome∠2.4 Other 7.3 Amparo Hernandez-Salazar, et al. Arch of Medical Research, Volume 37, Issue 7, October 2006, Pages ,

6

7 Your thought process immediately upon evaluating a patient: Is it Exanthematous and fixed > 24 hrs NO Go back to the basics YES Is it dusky? Are there targetoid papules, bullae, involvement of hands and feet? - NO Is there facial or palmar edema, rigors, malaise, lymphadenopathy, subacute/chronic appearance? NO YES YES SJS Drug-induced Hypersensitivity Syndrome Confirm with labs Are there pustules of the skin folds, fevers, rigors, thin sloughing? NO Is the patient in the Bone Marrow Transplant Unit? NO Proceed with Viral and Drug Etiologies YES YES AGEP Stay tuned for next lecture

8

9

10

11

12

13 Clinical Analysis of the patient, Morbilliform?

14 High Risk Low Risk Trunk + Facial involvement Trunk predominant Facial/Hand Edema Pustules Vesicles Duskiness Palmar/Plantar involvement Oral/Genital Involvement Spares Face No Pustules No Vesicles Spares palms and soles Spares mucosal surfaces

15 What features are important for your outpatient consultation? 1. Location? 2. Course? 3. Fevers? 4. Mucosal Findings? 5. Coloration? 6. Length of onset? 7. Minor morphologic features? 8. Biopsy Findings? 9. Medication History? 10.Immune Status, Transplant patient? Leukemia Patient?

16 Drago F 1, 2012 Dec;67(6): How do I tell if it is viral or drug?

17 How do I tell if an exanthem is viral or drug? Viral/Bacterial Drug Age Childhood Old Location A. Buttocks B. Face C. Hands and Face Morphology A. M&P&Petechia B. E& Pap or Pustular C. E&Vesicular D. True MP Viral Viral Drug Either Lymphadenopathy 8 1 -Usually viral Systemic Symptoms Fevers, Diarrhea, Pharyngitis etc. Enanthems 61 8 Time of Year Spring/Summer Fall/Winter Striking Pruritus 2 41 Drago F 1, :J Am Acad Dermatol Dec;67(6):1282-8

18 What other clues are available? Drago et al.. Br. J Dermatol. 2002; 147:255-60of cases.

19 Now you suspect drug, what next?

20 Drug Etiologies? Bigby et al. JAMA 1986, 256: Bigby Rates of cutaneous reactions to drugs. Arch Dermatol. 2001; 137,

21 Naldi et al.. Br. J Clin Pharmacol, 48, Drug Etiologies in outpatient setting?

22 Van der Linden et al. J Clin Epidemiol 1998; 51 (8) Antibiotic Etiologies in outpatients?

23 Where are the cephalosporins? Naldi et al. Br. J Clin Pharmacol, 1999; 48,

24 Don t forget delayed reactions to IV contrast Bircher et al Ann Allergy Asthma Immunol 2013; 111:

25 Are there drugs that we can likely rule out? Bigby et al JAMA 1986, 256:

26 What about cross-reactions?

27 What about cross-reactivity of Antibiotic Classes? Khan, Solendesky.. J Allergy Clin Immunol 2010; 125:S126-37

28 What about cross-reactivity of Antibiotic Classes? Khan, Solendesky. Drug Allergy. J Allergy Clin Immunol 2010; 125:S126-37

29 What about cross-reactivity of Antibiotic Classes? Khan, Solendesky. Drug Allergy. J Allergy Clin Immunol 2010; 125:S126-37

30 What is the typical time course for the exanthematous drug reaction? Fig 1 Chronology of drug-induced reactions. The separation at 1 hour into immediate or nonimmediate reactions does not sufficiently reflect the extension of the pathophysiologically determined immediate-type reactions up to 6 hours (Late) and the delayed type reactions Andreas J. Bircher, Kathrin Scherer HofmeierJournal of Allergy and Clinical Immunology, Volume 129, Issue 1, 2012,

31 . We propose that the term immediate for likely IgEmediated or pseudoallergic reactions presenting with urticaria, angioedema, bronchospasm, or anaphylaxis should encompass also these manifestations occurring at up to several hours (eg, 6 hours) and the term delayed be used for maculopapular and more severe exanthemas, which can start as early as 12 hours, even if many are mediated by T cells. Andreas J. Bircher, Kathrin Scherer HofmeierJournal of Allergy and Clinical Immunology, Volume 129, Issue 1, 2012,

32 Several factors influence the elicitation period: (1) History: This might be unreliable with regard to the exact occurrence of the initial signs of a hypersensitivity reaction. (2) Method of administration: Drugs, such as antibiotics or nonsteroidal anti-inflammatory drugs (NSAIDs), can elicit severe anaphylaxis within a few minutes on parenteral administration and can take up to 1 to 2 hours to do so after oral intake. Some drugs, such as proton pump inhibitors, typically elicit anaphylactic symptoms after several hours only. (3) Drug metabolites: These might take some hours to be formed until an IgE-mediated immediate reaction can start. (4) Cofactors (eg, effort, food intake, and comedications): These can accelerate or delay the occurrence of a drug hypersensitivity reaction.. Andreas J. Bircher, Kathrin Scherer HofmeierJournal of Allergy and Clinical Immunology, Volume 129, Issue 1, 2012,

33 . Fig 1 Systems involved in drug hypersensitivity. Werner J. Et al. Journal of Allergy and Clinical Immunology, Volume 127, Issue 3, Supplement, 2011, S74 - S81

34 Pharmacogenomics of Drug Eruptions Drug Indication Reaction Enzyme Other or Atrisk Population Abacavir HIV DiHS HLA-B*5701 Allopurinol Gout DiHS HLA-B*5801 Carbamazepine Epilepsy DiHS/TEN HLA-B*1502, HLA-B*1511 Asian descent Carbamazepine Epilepsy DiHS/TEN HLA-A*3101 Asians and European descent Phenytoin Epilepsy DiHS/TEN CYP2C9*3 Asian descent Penicillins, Clindamycin, Piroxicam Acute Infections, pain relief AGEP IL-36RN 1. Borroni RG. Role of dermatology in pharmacogenomics: drug-induced skin injury. Pharmacogenomics. 2015;16(4):

35 Fig 2 Drug and patient factors involved in the development of drug hypersensitivity. The main areas, stimulation of dendritic cells and their drug-induced maturation, formation of antigenic sites, preferential presentation of drugs/haptens by certain HLA a... Werner J. Et al. Journal of Allergy and Clinical Immunology, Volume 127, Issue 3, Supplement, 2011, S74 - S81 Journal of Allergy and Clinical Immunology, Volume 127, Issue 3, Supplement, 2011, S74 - S81

36 What about the SCARs?

37

38 What is the typical time course for DIHS Shiohara Clinic Rev Allerg Immunol (2007) 33:

39 Kardaun SH, Br J Dermatol 2013;169: Latency Symptoms

40 Kardaun SH, Br J Dermatol 2013;169: Drug etiologies for DiHS

41

42

43 Acute Generalized Exanthematous Pustulosis Peermohamed S,. Arch Dermatol. 2011;147(6):

44 Acute Generalized Exanthematous Pustulosis 1. Penicillins/ Cephalosporins 2. Clindamycin 3. Macrolides 4. Diltiazem 5. Hydroxychloroquine Dodiuk-Gad et al.semin Cutan Med Surg. 2014;33(1):2 9.

45 Next Patient

46 Etiologies for SJS/TEN? Schwartz. J Am Acad Dermatol. Elsevier Inc; 2013 Aug;69(2):173.e1 13;

47 What if you suspect a microorganism?

48 Etiology of Viral Eruption in Outpatient Setting Drago F 1, et al. J Am Acad Dermatol Dec;67(6):

49 What Micro studies should be ordered? - If URI or Mono-like symptoms Virus Serology PCR Tip Adenovirus IgA, IgG, or IgM S: 21-77% S: 93% SP: 100% Throat, URT swab CMV EBV IgM or IgG S: % SP: % Heterophile antibodies: S/SP: 86% and 100% RT-PCR: S: 100% SP: 97.7% S: 80% to 94%; SP: 90% to 99% PB PB HHV-6 HHV-7 HIV IgM: SP: 97.5% IgG (children): S: 95% SP: 76% Antigen/antibody combination immunoassay: HIV-1: S: 99.76% to 100% Sp S/SP: 100% and 92%, 58% and 100%, and 75% and 98%, respectively S: 95% SP: 98.8% SP: 100% PB PB PB Korman AM, et al. J Am Acad Dermatology. 2017;76(3):

50 What Micro studies should be ordered? - Acral/Oral Predominance Virus Serology PCR Tip Enterovirus S: 97.7% Coxsackie Echo SP: 93.3% IgM: S: 84.6% SP: 98.4% Not routinely used RT-PCR: S/SP: 92% and 81%, 100% and 83%, 95% and 81%, and 77% and 88%, respectively RT-PCR: CSF: S: 67% to 98% SP: 98% RT-PCR: S: 94.7%; SP: 97.4% Swab unroofed vesicle, oral, or anal mucosa. PCR best test, serologies unreliable! Korman AM, et al. J Am Acad Dermatology. 2017;76(3):

51 What Micro studies should be ordered? Arthralgias/Arthritis + Rash Virus Serology PCR Tip Zika IgM/IgG 100% RT-PCR 100% Send out to CDC PCR tests for all Chikungunya Dengue Parvovirus B19 IgM S: 96.9% SP: 98.3% IgM S: 96.9% SP: 98.3% IgM: S/SP: 65.6% to 91.4% and 93.6% to 97.3% RT-PCR: S/SP: 100% RT-PCR S: 91.4%, SP: 95.4% S: 92.7%, Sp 100% Serum three arboviral panels. Sample from peripheral blood Korman AM, et al. J Am Acad Dermatology. 2017;76(3):

52 What Micro studies should be ordered? -Un/Undervaccinated Virus Serology PCR of URT Tip Measles Rubella IgM S: 83-89% SP: % IgM S: % SP: % PCR S: 48% SP: 100% RT-PCR S/SP: 100% RT-PCR S: 83-95% SP: 100% CDC, viral send out CDC, viral send out Korman AM, et al. J Am Acad Dermatology. 2017;76(3):

53 The CDC and Send Out testing Print the CDC form specific for your patient PCR for Dengue/Chikungunya/Zika virus all run simultaneously due to shared habitats and clinical features Your patient can take the form to a local commercial laboratory.

54 What is the Prognosis

55 if Antibiotic associated? 21 % will clear in 1 weeks 84 % will clear within 2 weeks 16% require longer than 2 weeks Drago F 1 J Am Acad Dermatol Dec;67(6):

56 Long-term Patient Reported Outcomes after SCARs Graudins LV, Br J Clin Pharmacol. 2016;82:

57 What drug test methods are available?

58 Type of reaction Type of tests Immediate In vitro Specific IgE assays Flow cytometric BATs In vivo Skin tests Provocation tests Nonimmediate In vitro LTTs or LATs ELISPOT assays for analysis of antigen-specific, cytokine-producing cells In vivo Delayed-reading intradermal tests Patch tests Provocation tests Journal of Allergy and Clinical Immunology; (3): S67-73

59 Romano et al. J Allergy Clin Immunol Pract. 2014; 2:3-12.

60 Remaining Practice Gaps

61 How often are we right with the diagnosis? Changing medication Increased cost of Treatment 4 fold. Sastre et al.. J Allergy Clin Immunol. 2012; 129(2):566

62 What if we just provide an educated guess on the drug? Expert Agreement With defined Criteria Strength of agreement <0.20 Poor Fair Moderate Good Very good Naranjo C, Clin Pharmacol Ther 1981;30:

63 How to confirm the diagnosis of adverse drug eruption Definitive > 8 Probable 5-8 Possible 1-4 Doubtful < 1 Naranjo C, Clin Pharmacol Ther 1981;30:

64 How to confirm the diagnosis of DIHS Diagnostic criteria for DIHS/DRESS 1. Maculopapular rash developing >3 weeks after starting therapy with a limited number of drugs 2. Lymphadenopathy 3. Fever (>38 C) 4. Leukocytosis (> /l) Atypical lymphocytosis Eosinophilia 5. Hepatitis (ALT>100U/l) 6. HHV-6 reactivation The diagnosis is confirmed by the presence of five of the six criteria above Shiohara.Clinic Rev Allerg Immunol (2007) 33:

65 What is the value of a skin biopsy? Histopathology revealed only a nonspecific pattern consisting of a scarce, mainly perivascular, lymphohistiocytic infiltrate. This was helpful only in cases of AGEP, in which typical spongiform superficial pustules with focal necrotic keratinocytes and papillary edema were observed. Drago F 1. et al J Am Acad Dermatol Dec;67(6):

66 Seitz CS, J Am Acad Dermatol 2013;69: What is the value of a skin biopsy?

67 Seitz CS, J Am Acad Dermatol 2013;69: What is the value of a skin biopsy?

68 What is the value of a skin biopsy? Cohen s Kappa -.29 Seitz CS, J Am Acad Dermatol 2013;69:721 8.

69 Key points: 1. Look for specific features to guide your work-up or counseling 2. Differentiate high-risk features as your first step. 3. Perform viral/bacterial testing based on your patients coexisting symptoms 4. You do not have any strong support for laboratory testing except penicillin 5. Don t forget to back and look through the literature, including clinical trials.

70 High Risk Low Risk Trunk + Facial involvement Trunk predominant Facial/Hand Edema Pustules Vesicles Duskiness Palmar/Plantar involvement Oral/Genital Involvement Spares Face No Pustules No Vesicles Spares palms and soles Spares mucosal surfaces

71 Thank you for your time Ben Kaffenberger, MD