(10/6) Thambi Lecture: Drug Allergies ---- Alrighhhh?? Alrigh. Is it really drug-related allergies?

- Allergic Reaction: ADR mediated by the immune system - Pseudoallergic Reaction: ADR with similar clinical presentation to allergic reactions, but without the involvement

of the immune system Type 1: Immediate in onset, and mediated by: IgE and Mast Cells

- This is the most common type of allergic drug reaction, usually requiring previous exposure (induction) and the response is present on re-exposure (elicitation)

- Sx: Urticarial rash “Hives” (most common), Pruritus, flushing, angioedema of the face/extremities/laryngeal, GI symptoms, Hypotension, Anaphylaxis.

o The Urticarial rash may present in characteristic wheals. Or, more related to drug-induced rashes, may present as several small demarcated lesions – aka the Maculopapular Rash

o Fool’s Gold. FEVER IS NOT seen in Type 1 Reactions - Anaphylaxis: Acute life-threatening allergic reaction involving multiple organ systems. Under-recognized and

Under-treated. Goal: Prevent anaphylactic shock o Sx: 80-90% Skin (Flushing, Urticaria, Angioedema), 70% Respiratory (Nasal congestion, cough,

tightness of throat and chest, SoB), 40% GI (nausea, crampy abdominal, D/V), 35% CV: Hypotension § Angioedema: Affects areas with loose connective tissues (face, mouth, throat, larynx, bowels)

• Mast-Cell Mediated: Type 1 HSR, occurs after exposure, usually with bronchospasm • Bradykinin-mediated: Most commonly associated with ACE-I à NOT allergic. This

often has a delayed onset (sometimes years) • Angioedema of the Tongue: Unilateral is often due to ACE-I, so check that first, but

allergic cases do occur as well. o Progression: Rapid onset, within 30 minutes of antigen exposure. 2 Potential time-courses

§ Biphasic Anaphylaxis: After recovery, recurrence after 6-10 hours. Thus, Must monitor patients! § Protracted Anaphylaxis: Though rare, this involves symptoms persisting for >24 hours

o Dx: Criteria Developed, based on whether exposure is: (1) Unknown, (2) Likely, (3) Known

Pitfalls to diagnosis: The signs are non-specific

- Skin manifestations absent in 10-20% o Especially if H1 antihistamine

was taken - Sedated, confused, or demented patients

are unable to voice signs and symptoms Cx? ANY DRUG CAN CAUSE ANAPHYAXIS

- Commonly implicated drugs: Beta-lactams, Cephalosporins, Sulfonamides, NMJ Blocking agents, Chemotherapy Type 2: Delayed in onset, and caused by IgG-mediated cell destruction

- Mechanism: Drug will bind to certain cell types and act as antigens. It will be targeted for lysis by macrophages, thus this is a cytotoxic reaction. Symptoms generally are delayed, appearing 5-8 days after exposure (could be sooner). IT HAPPENS TO A SPECIFIC CELL LINE

- Clinical Examples: Hemolytic Anemia (RBC), Thrombocytopenia (Platelets), Leukopenia (WBC), Neutropenia (Neurtrophils)

o Heparin-Induced Thrombocytopenia (HIT): Paradoxical increased risk for clotting.

§ à Ab activates platelets by binding to platelet factor 4. RES tries to eliminate platelets, resulting in low platelet counts, but still high risk of life & limb threatening clots. Require anticoagulation with non-heparinoid anticoags

Type 3: Delayed in onset, and caused by IgG-Drug Immune complex deposition and complement activation - Mechanism: Free IgG or IgM binds to freely circulating antigen (like a drug) to form an immune complex that

precipitates in tissues, binding to inflammatory cells and activating complement. The inflammatory response will be initiated. This reaction could be delayed by over 1 week!

- Clinical Examples: Serum Sickness (fever, urticarial rash), Vasculitis (Bleeding within the skin, Big Purpuras and Little Petechiaes), and Drug Fever – can also occur with Type 4 reactions

- Cx: Similar to Type 2, this reaction generally occurs following high dose, long-term, or recurrent drug exposure o Serum Sickness is commonly caused by antibiotics, antivenom, and Blood Transfusions o Vasculitis: Most commonly caused by Propylthiouracil (PTU)

- Dx of Drug Fever: Due to the diagnostic dilemma of this example of Type 3 HSR, we will focus on it o Sx: Fever that doesn’t go away but “feeling inappropriately well”, Fever 102-104 o Can distinguish Drug Fever from Infectious Fever by checking for the presence of Eosinophilia!

Type 4: Delayed in onset, and T-Cell mediated. Famously known as “Delayed Hypersensitivity Reactions” - Sx: Typically presents with skin reactions 1-3 weeks after treatment. Contact Dermatitis, Maculopapular

Eruptions, Stevens-Johnsons Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

o Why the Skin? The skin is a repository for a large number of T Cells - SJS & TENs: Begins with fever and malaise, will be rapidly followed by erythematous/purpuric macules/plaques

o Will progress to epidermal necrosis and sloughing. It is essentially an allergic reaction to the entire thickness of skin. Usually affecting the mucosa first.

o SJS<10% BSA, TEN>30% BSA. 10-30 = SJS-TEN o Implicated Drugs: Antibiotic Sulfonamides, Beta-lactams, NSAIDs, Allopurinol o Tx: Since this is a delayed reaction, we can prevent progression by d/c med.

- DRESS: A widespread rash with fever, resulting in single or multiple organ failure o A severe reaction, where the Liver is the most commonly involved organ. While not

all cases are associated with eosinophilia, most are. AKA: Drug-Induced Hypersensitivity Syndrome (DiHS)

o Implicated Drugs: Antiepileptics are the number 1 cause – Phenytoin, Phenobarb, Lamictal Drug-Induced Autoimmunity – The unclassified Drug Allergies, reactions that don’t quite fit a category

- Aminopenicillin Reaction: Occurs after exposure to Epstein-Barr virus. o Drug: Ampicillin/PCN/Amoxicillin à Boom Mononucleosis “Mono”. Occurs 7-14 days after starting

Antibiotic. This reaction is not likely to occur on rechallenge after resolution of infection o Sx: Red, itchy, maculopapular rash involving the upper extremities and trunk

- Drug-Induced Lupus (DILE) This reaction has a mechanism that is largely unknown, with an onset weeks-years o Sx: Anthralgia (joint pain), Myalgia (muscle pain), Erythema (Redness), Positive Anti-nuclear Ab (ANA)

§ 75-95% of patients with DILE have + Anti-histone Ab. § Patients with negative anti-dsDNA and + anti-Histone Ab à Good chance they have DILE

o Tx: Resolves rapidly after drug d/c o Implicated Drugs: The below and SHIPP

§ High Risk: Procainamide, Hydralazine § Moderate Risk: Quinidine § Low/Very Low Risk: Minocycline, Sulfasalazine, Phenytoin, HMG-

CoA Inhibitors - Interstitial Nephritis: We spent so little time on this, meh, just know it’s PPIs

o Sx: Often associated with Eosinophilia o Implicated Drugs: PPI, Beta lactams, Sulfonamides, Vanco, NSAIDs, Rifampin

- Drug-Induced Phototoxicity/Photoallergy: Phototoxic injury to cells in the skin and a sunburn-like Reaction that may blister in the exposed areas. We are unsure whether this is immune related. Dr Thambi was hesitant on whether or not to include this in the lecture. So… yea

o Implicated Drugs: Tetracycline (Doxycycline hurt that poor rower’s hands), Sulfonamides, Amiodarone Common Bandit: Beta-Lactams: Most common cause of allergic drug reactions (10% of patients claim)

- Sx: All four types of HSR can occur. The most common with PCN are Urticaria, Pruritus, and Angioedema - Dx: PRE-PEN – PCN Skin Testing using Penzylpenicilloyl polylysine (metabolite of PCN – the common threat)

o Tests for IgE reaction to penicillins by epidermal injection of PRE-PEN. No Rxn? à Intradermal INJ o Concurrent admin with Histamine and NS is advised when ID INJ the PCN-G at 10,000 units/ml

§ Have E and DPH syringes readily available. o Still No reaction? Done. à 96-99% the patient will not have an allergic reaction to full dose.

- Cross-Reactivity: With Cephalosporins: There is controversy over this, likely due to PCN impurities <1980 leading to cross-sensitivity. Studies have suggested only 0.3% to 9% of PCN allergies are allergic to Cephalo

o 1st Generation Cephalosporins: Keflex – have similar side chains to the Aminopenicillins (ampicillin,amox). These agent have higher rates of cross-reactivity.

o 2nd, 3rd, 4th generation cephalosporins have very low cross reactivity - Cross-Reactivity: With Carbapenams: Wide-range of cross reactivity, 0-11% of PCN allergy people had allergic

reaction to carbapenem. o It is suggested to do PCN skin testing. If negative, highly unlikely the allergy will occur to carbapenem

- Cross-Reactivity: With Aztreonam: Ceftazidime has an identical side chain to that of Aztreonam, and there is a significant risk of cross-reactivity

- Guide to Dosing a PCN-Allergy Patient with Cephalos and Carbapenems o (1) Determine if the pt has received a cephalo or carbapenem since the time of initial PCN reaction

§ Yes? Without a reaction? Nice! à Give the Med. No? à See below o (2) How bad was your PCN reaction?

§ Mild/molderate? NICE! à Give the med • Woah what? Over 10 years ago PCN reaction – allergies diminish over time. Chill

§ Anaphylaxis or severe? à DON’T GIVE WITHOUT DESENSITIZING THIS ATOPIC FIEND Common Bandit: Sulfonamides: Second most common cause of allergic drug reactions

- Culprit: Sulfonamides with arylamine side chain. Coincidentally, only Antibiotic sulfonamides contain arylamine side chains

- Non-antibiotic Sulfonamides: Like furosemide, glyburide, HCTZ, Suma, cross-reactions are rare to nonexistent. Sulfa allergy? Not allergic to these.

- Sx: Delayed cutaneous maculopapular rash within 3 days. Sulfonamides are the most common cause of SJS and TENs.

- Tx: D/C drug immediately. Common Bandit: Aspirin (ASA): An acute Type 1 HSR

- Sx: - Samter’s Triad – Cross-reaction with NSAIDs is common as well o (1) Hypersensitivity Reaction o (2) Asthma Exacerbations o (3) Rhinitis +/- Nasal Polyps

Common Bandit: Anticonvulsants and DRESS – “Anticonvulsant Hypersensitivity Syndrome” - As discussed earlier, Type 4 Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is characterized by

fever, rash, and internal organ involvement. Quick hint, Eosinophilia is common. May develop into SJS or TEN - Concomitant use of valproate + lamotrigine/lamictal significantly increases the risk of hypersensitivity

o (Valproate inhibits lamictal’s metab) When used together, we want to slowly increase lamictal’s dose. HLA Type and how it is a Risk Factor for Drug-Allergies

- Recall, Human Leukocyte Antigen is the gene for MHC. Certain HLA types are associated with allergic rxns. - HLA Testing: It is a black box warning for many drugs! Abacavir, Carbamazepine, Allopurinol, Phenytoin

Tx: Allergic Reaction - Step 1: Identify and d/c suspected offending agent - Tx: Urticaria: Usually not to bad once you d/c the offending agent, but if still crying, treat the symptoms

o DRUG: H1 Antihistamines (DPH), H2RA (Famotidine, Ranitidine), Glucocorticoids o DRUG: Epinephrine (E) may be given if there is a history of anaphylaxis.

Tx: Anaphylaxis- This is a life-threatening event, give immediate treatment - Step 1: Identify and d/c the suspected offending agent - Immediate Management: àBOOM, IM injection of E

o Try to maintain O2 saturation at >92%... ha what? à Tell whoever to do supplemental O2 or intubation o Lay the patient down on their back and keep their legs raised – causing gravity to prioritize the central

compartment and heart. This is common for Shock tx. It helps to raise the BP. o à Slam ‘em with 0.9% NaCL 1-2 L wide open, repeat as needed. o Monitor their BP, HR, RR, O2 Sat, I/Os

- Hey, tell me about this ‘E’ (Thambi refers to it as Epi)

o Mainstay of medication therapy – DON’T YOU DARE DELAY IM E ONCE ANAPHYLAXIS IS Dx! o There are no contraindications to E in the tx of anaphylaxis. Half of the deaths occur within 1 hour of

anaphylaxis onset. So it’s probably a good idea to IM INJ E NOW!!!! o Dosing: IM/SC: 0.3mg, of 1mg/mL every 3-5 minutes until improved. IM into mid/outer thigh for faster

onset. By the way, this dose is too high for IV admin. It’ll kill them o MoA: a and b agonist – Vasoconstriction will increase BP and the drug will inhibit further mediator

release. It will also induce bronchodilation - Adjunctive Therapies to E: Adjunctive therapies are adjunctive therapies, they’re not substitutes. GIVE E!

o Urticaria: Give Benadryl (DPH) 25-50mg IVP, Ranitidine 50mg IVPB o Respiratory Sx: Give Bronchodilators, Albuterol nebulized solution, Ipratropium o Late Phase Reaction: Give Corticosteroids, helps prevent the late phase reaction, but has little effect on

the acute symptoms. The onset of action is 4-6 hours. Drug: Methylprednisolone 125-250mg IV q6h § à Transition to oral prednisone when patient stabilizes.

- Recovery from Anaphylaxis: Monitor patient for 4-6 hours, and begin the transition to pertinent oral meds. o Educate patient on causative agents, methods to avoid exposure, and enter the event into the EMR o Consider self-treatment devices: EpiPen 0.3mg for IM use, EpiPen Jr for Kids <30kg

§ When using epipen, remove caps from either side, and hold injector in place for 3 seconds (it used to be 10 seconds, but the kids thrashed around and messed up the needle like a fishhook)

Tx: Refractory Anaphylaxis/Hypotension - E Infusion: Slow IV Infusion, 1-4mcg/min, by using a more dilute dosage form 0.1mg/mL

o Titrate to maintain SBP >90mmHg - Vasopressors (Dobutmine and Dopamine (DA)) - IV Fluids: NS

(10/9) Hanakahi Lecture: Immunity to Tumors The Potential fates of Cancer, and the role of immunoediting

- Elimination: Immune system wins. Innate and adaptive immune cells and cytokines recognize the transformed cells and destroy them. In this mechanism of immunoediting, there are few regulatory cells, just lotsa killing

o Proof of Principle: Various Immune System component knockout mice were more susceptible to carcinogenic-induced tumors

- Equilibrium: The Tumor cells chill and learn. The surviving tumor variants may persist and the immune cells/molecules simply prevent tumor growth. During this latency period, there will be 3 possible outcomes for the tumor cells, (1) be eradicated, (2) persist but not progress, (3) Escape immune pressure

- Escape: The tumor has evaded the immune system, CANCER. Additional mutations result in evasion of recognition/killing/control by the immune system.

o à Major transition occurs where tumor cells inhibit the function of effector immune cells. They recruit more regulatory immune cells. Thus, LESS killing cells and MORE regulatory cells. This produces an immunosuppressive tumor microenvironment

- Immunotherapy seeks to treat the ESCAPE stage. Onwards and upwards Cytotoxic T Cells (Tc), CD8+

- Most cells, “all nucleated cells”, express MHC Class I, therefore CD8+ cells monitor virtually all cell types - Activation: CD8+ T Cell recognizes specific MHC I-Ag combination

o CD4+ Th independent: Direct interaction with MHC I expressing cell (APC or just virally infected cell) o CD4+ Th Dependent: APC-CD4+ interactions produce IL-2, inducing CD8+ Tc Cell activation,

resulting in destruction of the target cells expressing MHC I associated antigenic peptides - Formation of the CTL Immunological Synapse

o TCR recognition of MHC I-Ag is the first part of forming the synapse. Signaling through closely associated CD3 begins to elicit the cellular response. Adhesion molecules help establish close proximity (ICAM-1, and LFA-1)

- Killing Mechanisms: o Fas/FasL: Interaction of these cell surface proteins induces caspase activation à eventual apoptosis o Perforins: The cytotoxins that form a polyperforin channel à Cell lysis and death

§ How? Perforin monomer, when in the presence of high [Ca2+] is soluble, and will be able to fuse to and be inserted within the target membrane. Other Perforin monomers similarly enter, and together aggregate to form a pore. This is the Homopolymeric pore lesion. Hydrophilic on the