Good Morning! Happy Friday!

1. Good Morning!Happy Friday! Friday, July 26th 2013

2. HPI • 9yo M w/ dev delay, epilepsy p/w increasing seizure activity despite recent medication changes • Seizures range from partial to tonic clonic with a majority being focal with eye movements. • Mom denies URI symptoms, fevers, rashes, changes in urine, diarrhea, vomiting or sick contacts.

3. HPI continued • BHx: born premature at 24weeks, NICUx3 months, mom with viral infection • PMH: developmental delay, ambulates and feeds with help, left sided weakness, minimally verbal, epilepsy since 4y/o • PHS: VNS placed 3/2013. VP shunt placed 2007 then removed shortly after • Allergy: Vancomycin Red mans. • Home Medications:Topamax, Keppra, Clonazepam, Lamictal, Clonidine, Melatonin • FMH: diabetes and hypertension

4. HPI • Infectious work up initiated, no abx started • Pt admitted and loaded with Depakote IV on HD#1 • HD#2 pt developed progressive facial flushing and repetitive sneezing and emesis x 2. Erythematous macular rash erupted on his arms and trunk.

5. PE • PE: VS: HR: 90 RR: 14 BP: 100/67 Temp: 98.8 weight: 28kg • Gen: Awake NAD, flushed cheeks, lying in bed • HEENT: Throat clear, TMs clear • CV: RRR no murmur • Resp: CTA b/l • Abdomen: soft NTND bowel sounds present • Skin: erythematous diffuse macular rash on arms and trunk

6. Semantic Qualifiers

7. HPI • Problem Definition 9 yo M with developmental delay and epilepsy, admitted with progressive seizure activity refractory to home medications, now with acute onset of flushing, macular rash on trunk and upper extremities and emesis • Differential Diagnosis

8. Drug Reactions

9. Types of Drug Reactions • Type A: Can affect any individual given a sufficient dose and exposure • Predictable reactions based on the pharmacologic principles of the drugs • Examples: • Diarrhea from antibiotics • Gastritis from NSAIDs • Nephrotoxicity from aminoglycosides • Type B: Hypersensitivity reactions that occur in a subgroup of susceptible patients • Symptoms are different from the pharmacologic actions of the drugs • Usually cannot be predicted • ‘Drug Allergies’ • 4 types PREP Question

10. Prep Question • A 14yo boy who w/ CF p/w fever, cough, and respiratory distress. On PE, his temp is 38.9°C, RR 28, HR 90 bpm, BP 116/74, and pox 91% on RA. CXR reveals bilateral infiltrates. After collecting blood and sputum specimens for culture, you initiate treatment with IV ceftazidime and tobramycin. Of the following, the MOST likely adverse effect that can occur with this treatment regimen is • A. Achiles tendonitis D .interstitial pneumonitis • B. Aplastic anemia E. ototoxicity • C. gallbladder sludge

11. Prep Question • A 14yo boy who w/ CF p/w fever, cough, and respiratory distress. On PE, his temp is 38.9°C, RR 28, HR 90 bpm, BP 116/74, and pox 91% on RA. CXR reveals bilateral infiltrates. After collecting blood and sputum specimens for culture, you initiate treatment with IV ceftazidime and tobramycin. Of the following, the MOST likely adverse effect that can occur with this treatment regimen is • A. Achiles tendonitis D .interstitial pneumonitis • B. Aplastic anemia E. ototoxicity • C. gallbladder sludge

13. Type I Hypersensitivity Reactions • Immediate in onset • Typically within 1 hour of administration • Mediators? • IgE, mast cells, basophils • Release vasoactive mediators • Clinical Features: • Urticarial rash • Pruritis, flushing, angioedema, wheezing, GI upset, hypotension • Most severe presentation? • Anaphylaxis

14. Prep Question • The parents of a 10-yo boy who has a peanut allergy ask your advice on treatment of food allergy reactions at school. Last year, their son started itching diffusely and had difficulty breathing during lunchtime after accidentally eating some of his friend's chocolate candy bar that contained peanuts. The child is allowed to carry his own self-injectable epinephrine at school. His current weight is 90 lb (41 kg). Of the following, the BEST advice for the child, if a similar situation occurs, is to • A. Have the school call emergency services (911), who should evaluate and administer epinephrine if needed • B. Have the school nurse observe the child for 10 to 15 minutes while calling his parents • C. Immediately administer 0.15 mg of self-injectable epinephrine • D. Immediately administer 0.30 mg of self-injectable epinephrine • E. Take an oral antihistamine immediately

15. Prep Question • The parents of a 10-yo boy who has a peanut allergy ask your advice on treatment of food allergy reactions at school. Last year, their son started itching diffusely and had difficulty breathing during lunchtime after accidentally eating some of his friend's chocolate candy bar that contained peanuts. The child is allowed to carry his own self-injectable epinephrine at school. His current weight is 90 lb (41 kg). Of the following, the BEST advice for the child, if a similar situation occurs, is to • A. Have the school call emergency services (911), who should evaluate and administer epinephrine if needed • B. Have the school nurse observe the child for 10 to 15 minutes while calling his parents • C. Immediately administer 0.15 mg of self-injectable epinephrine • D. Immediately administer 0.30 mg of self-injectable epinephrine • E. Take an oral antihistamine immediately

16. Type I Hypersensitivity Reactions • Commonly-implicated drugs • Beta lactams • Neuromuscular blocking agents • Quinolones • Platinum containing chemotherapy • Foreign proteins • Cetuximab, rituximab

17. Type II Hypersensitivity Reactions • Uncommon • Involve antibody-mediated cell destruction • Drug binds to surfaces of certain cell types and act as antigens • Subsequent binding of antibodies results in the cell being targeted for clearance by macrophages • Variable involvement of complement activation • Requires the presence of high titers of preformed drug-specific IgG (or IgM) antibodies • Made by only a small percentage of individuals • Usually in the setting of high-dose, long-term or recurrent drug exposure

18. Type II Hypersensitivity Reactions • Cell types most commonly affected? • RBCs, WBCs, platelets • Symptoms are delayed • Typically appear at least 5-8 days after exposure; can be longer • Clinical manifestations • Hemolytic anemia • Dyspnea, fatigue, pallor, jaundice, dark urine, hyperdynamic state (ie bounding pulses, palpitations) • Neutropenia • Fever, stomatitis, pharyngitis, pneumonia, sepsis • Thrombocytopenia • Petechiae, mucosal bleeding, splenomegaly/hepatomegaly

19. Type II Hypersensitivity Reactions • Drugs implicated • Hemolytic anemia • Cephalosporins, penicillins, NSAIDs, quinine/quinidine • Neutropenia • Propylthiouracil (PTU), antimalarials, flecainide • Thrombocytopenia • Heparin, abciximab, quinine, sulfonamides, vancomycin, gold, beta-lactams, carbamazepine, NSAIDs

20. Type III Hypersensitivity Reactions • Also uncommon • Mediated by antigen-antibody complexes • Drug acts as soluble antigen and binds to drug-specific IgG forming small immune complexes that precipitate in various tissues • Complexes bind to receptors on inflammatory cells and/or activate complement  inflammatory response • Timing of response • >1 week (need adequate time to develop significant quantity of antibody) • Which tissues are typically affected? • Blood vessels, joints, renal glomeruli

21. Type III Hypersensitivity Reactions • Clinical presentation: several forms • Drug fever • Can be the sole symptom or prominent symptom • Can be accompanied by nonurticarial rash or other organ involvement • Common drugs: azathioprine, sulfasalazine, minocycline, bactrim • Vasculitis • Palpable purpura and/or petechiae, fever, urticaria, arthralgias, LAD, elevated ESR, low complement levels • Common drugs: penicillins, cephalosporins, sulfaonamides, phenytoin, allopurinol • Serum sickness • Classic: Fever, urticarial or purpuric rash, arthralgias, and/or acute glomerulonephritis • Can have just 1 or 2 features • Other findings: LAD, low complement levels, elevated ESR • Common drugs: penicillin, amoxicillin, cefaclor, bactrim

22. Type IV Hypersensitivity Reactions • Not mediated by antibodies • Involve the activation of what cells? • T-cells • Other cell types can be involved (macrophages, eosinophils, neutrophils) • Timing • Delayed at least 48-72 hours and up to days-weeks after exposure • Clinical presentation: • Prominent skin findings! • The skin is home to a large number of T cells

23. Type IV Hypersensitivity Reactions • Types of Type IV reactions • Contact dermatitis • Topically applied drugs • Erythema, edema, vesciles or bullae (can rupture and cause crust) • Morbilliform eruptions • Generalized and symmetric maculopapular eruption • Lacks mucosal involvement

24. Type IV Hypersensitivity Reactions • SJS/TEN • Onset is usually 1-3 weeks • Fever, mucocutaneous lesions  necrosis and sloughing • Distinguished by the severity and percentage of body surface involved • SJS <10% BSA • TEN >30% BSA • Drugs involved • Allopurinol, sulfonamides**, PCN, Cephalosporins, antipsychotics, antiepileptics, NSAIDS • Can also be caused by infection (mycoplasma, HSV) or malignancy

25. Starts as erythematous macules that develop bullous centers • “Atypical target lesions” with irregular shapes and sizes, some areas of confluence • + Nikolsky sign SJS/TEN: Skin Findings

26. Mucosal erosions at 2 or more sites • Stomatitis • Conjunctivitis • Urethritis Mucosal Findings

27. Erythema Multiforme • Acute, immune-mediated condition characterized by the appearance of distinctive target-like lesions on the skin • EM major: EM with mucosal involvement • EM minor: EM without mucosal involvement • EM major and SJS are DIFFERENT diseases with distinct causes • 90% infectious cause: Mycoplasma pneumoniae and HSV* • 10% medications • Systemic symptoms uncommon in mild EM, but can include fever, malaise, myalgia, respiratory symptoms

28. Type IV Hypersensitivity Reactions • Drug reaction with eosinophila and systemic symptoms (DRESS) • Also known as Drug-induced Hypersensitivity Syndrome • Severe drug hypersensitivity involving rash, fever, and multi-organ failure • Liver, kidneys, heart, lungs • Drugs responsible: antiepileptics, minocycline, allopurinol, dapsone

29. DRESS • Severe type IV hypersensitivity reaction • Timing: 3-8wks after drug administration • Clinical manifestations: • High fever • Eosinophilia • Lymphocyte activation • Facial edema • Skin eruption • Maculopapular rash • Erythroderma followed by exfoliative dermatitis • Rarely, skin manifestations may be minimal • Lymphadenopathy • Multivisceral involvement

31. Treatment • Glucocorticoids • Close monitoring with slow taper • Symptoms may re-flare weeks later • IVIG • antivirals

32. Type IV Hypersensitivity Reactions • Higher risk of some type IV drug allergy reactions during generalized viral infections • EBV with amoxicillin • CMV with any antibiotic • HHV6 with antiepileptics • HIV with trimethoprim-sulfamethoxazole

33. Genetics Conference 9-10am Dr. LaCassie – Genetic Testing NOON CONFERENCE: Shock with Dr. Desselle Thank you!!