CC_AllergicReactions_McCall - 2023.pptx

Allergic Reactions Stephen H. McCall, PharmD, BCPS, BCCCP | [email protected] Assistant Professor of Pharmacy Practice PHA 5373|IS X – Critical Care July 19th, 2023 Objectives  Describe the different types of allergic reactions and antibodies associated  Identify common offending agent...

Allergic Reactions Stephen H. McCall, PharmD, BCPS, BCCCP | [email protected] Assistant Professor of Pharmacy Practice PHA 5373|IS X – Critical Care July 19th, 2023 Objectives  Describe the different types of allergic reactions and antibodies associated  Identify common offending agents for patients presenting with allergic reactions and create a pharmacotherapy treatment plan once identified  Distinguish between the different types of allergic reactions based upon patient presentation and history  Outline the basic steps of penicillin skin testing and drug desensitization and their role in therapy Readings and Resources  Pharmacotherapy: a Pathophysiologic Approach, 11th ed. • Ch. e102 “Function and Evaluation of the Immune System” • Ch. E104 “Drug Allergy”  Applied Therapeutics: the Clinical Use of Drugs, 11 th ed. • Section 6, Ch. 32 “Drug Hypersensitivity Reactions” Before We Start What is the first line treatment for an anaphylactic reaction? a) Methylprednisolone b) Famotidine c) Diphenhydramine d) Epinephrine Subset of Adverse Drug Events  Type A  Type C • Predictable • Chronic side effects • Usually dose dependent • Related to duration of therapy • Related to pharmacologic action  Type D  Type B • Rare side effects • Unpredictable • Delayed onset • Often dose independent • Usually dose-related • Related to individual’s immunologic response or genetic differences Drug Allergy  “Immunologically mediated hypersensitivity reaction to a drug in a sensitized person” - WHO  Immune system hyper-response • Host tissue damage • Manifests as organ-specific or generalized systemic reaction  Factors affecting immunogenicity • Size of molecule (>1000 Da) • Haptens • Biological agents Drug Allergy (per ICON)  The International CONsensus (ICON) on Drug Allergy  Proposed delineation • Drug allergy  Definite immune mechanism • Drug hypersensitivity reaction (DHR)  Clinically resemble allergy  May or may not be immune mediated ICON Classification Recommendation  Immediate • Production of IgE-mediated response • Typically within one hour of reexposure • Manifestations  Angioedema, bronchospasm, anaphylaxis, or anaphylactic shock  Nonimmediate • Typically mediated by T cells • May occur >1 hour after initial exposure, up to weeks or months • Manifestations  Maculopapular exanthems, delayed urticaria Examples DRUG ALLERGIES  Anaphylaxis  Halothane hepatitis  Stevens-Johnson syndrome (SJS)  Heparin-induced thrombocytopenia  Allopurinol hypersensitivity syndrome  Serum sickness DRUG HYPERSENSITIVITY REACTIONS  Isolated urticaria after radiocontrast media  Aspirin-induced asthma  Opiate-related pruritis  Flushing after vancomycin infusion Mechanisms of Drug Reaction- Theories/Concepts  Prohapten/Hapten Concept • Assumption that small-molecular-weight molecules (<10 kDa) do not have ability to serve as antigens on their own • Most drugs <1,000 kDa  Except polypeptide compounds  P-i Concept • Pharmacologic interaction of drugs with immune receptors that does not require initial binding of drug • T cell mediated Predisposing Factors  Drug-related • Dose • Frequency • Route of administration  Patient-related • Age and sex  Children less likely to become sensitized  Females > males • Genetics • Associated illness • Previous drug administration Clinical Features of Allergic Drug Reactions  Unpredictable  Occur in susceptible individuals  No correlation with known pharmacologic properties of the drug  Require induction period on primary exposure but not upon re-administration  Can occur with doses well below therapeutic range  Can affect most organs • Most commonly involves the skin  Most commonly manifests as erythematous or maculopapular rash • Also includes angioedema, serum sickness syndrome, anaphylaxis, and asthma  Occur in small proportion of population (10-15%)  Disappear upon cessation of therapy, reappear after a small dose of suspected drug of similar chemical structure  May be able to desensitize Classification of Allergic Drug Reactions Type Descriptor Characteristics Typical Onset Drug Causes I Immediate (IgE mediated) Allergen binds to IgE on basophils or mast cells, resulting in release of inflammatory mediators Within 1 hour (may be 1-6 hours) Penicillin anaphylaxis, angioedema, blood products, polypeptide hormones, vaccines, dextran II Delayed; cytotoxic Cell destruction due to cell-associated antigen, initiated cytolysis by IgG and complement, likely includes blood elements Typically >72 hours to weeks Penicillin, quinidine, quinine, heparin, thiouracils, sulfonamides, methyldopa III Delayed; immune complex Antigen-antibody (IgG or IgM) complexes form -> deposit on blood vessel walls & activate complement = serum sickness-like syndrome or vasculitis >72 hours to weeks May be caused by penicillins, sulfonamides, minocycline, hydantoins IV Delayed; T cell mediated Antigen causes activation of T lymphocytes -> releases cytokines & recruit effector cells >72 hours Type IV Reactions Type Descriptor Characteristics Typical Onset Drug Causes IV IVa Th1 cells & interferon-γ, monocytes and eosinophils respond to antigen 1-21 days Tuberculin reaction, contact dermatitis IVb Th2 cells, interleukin-4 and interleukin-5 respond to antigen 1-6 weeks Maculopapular rashes with eosinophilia IVc Cytotoxic T-cells, perforin, granzyme B, FasL respond to antigen 4-28 days Bullous exanthems; fixed drug eruptions IVd T cells and interleukin-8 respond to antigen >72 hours Acute generalized exanthematous pustulosis Reaction Types Visually Explained  Type I • https://youtu.be/2tmw9x2Ot_Q  Type II • https://youtu.be/kLaUz58CBMc  Type III • https://youtu.be/0T_SAXyMs_c  Type IV • You are on your own Type I: Immediate Hypersensitivity  IgE mediated  Initial exposure: production of specific IgE antibodies • Expressed on surface of mast cells in tissue and basophils in blood  Reaction occurs upon re-exposure • Release of histamine, tryptase, leukotrienes, prostaglandins, cytokines Type I: Immediate Hypersensitivity  Manifestations • Pruritus and urticaria, bronchospasm, respiratory distress, laryngeal edema, circulatory collapse, or death • May be limited to single organs or involve multiple organs simultaneously  Single organ involvement: nasal mucosa (rhinitis), respiratory tract (asthma), skin (urticaria) or GI tract  Multiple organ involvement = anaphylaxis Anaphylaxis No known or unknown allergen exposure Acute onset of skin signs (urticaria, angioedema) Likely exposure to allergen Known exposure to allergen Rapid development of >2 of following: ↓BP Plus >1 of following: Skin/mucosal tissue Respiratory compromise ↓BP or symptoms of end organ dysfunction Respiratory compromise ↓BP or associated symptoms Persistent GI symptoms Treatment of Anaphylaxis: 1st Line  Epinephrine • Adults  0.01 mg/kg (1 mg/mL) max 0.5 mg IM q5min PRN  Progressing to cardiac arrest: 0.1-0.3 mg (1 mg/10 mL) IV x3 minutes  IV rate 4-10 mcg/min  0.3-0.5 mg (1 mg/10 mL) intratracheally q10-20 minutes PRN • Pediatrics  0.01 mg/kg (1 mg/mL) max 0.3 mg IM q5-15min  May administer IV for severe reactions  Oxygen  Albuterol • 0.5 mL (0.5% solution in 2.5 mL saline) via nebulizer  IV fluids • 1 L NS over 5-10 min, q20-30 minutes PRN Treatment of Anaphylaxis: 2nd Line  Antihistamines • H1 antagonists • H2 antagonists  Corticosteroids • Hydrocortisone • Methylprednisolone  Dopamine  Norepinephrine  Glucagon Preventing Recurrence of Anaphylaxis  Assess for possible recurrence • Peanuts, shellfish, medications  If recurrent exposure likely, autoinjectable epinephrine should be prescribed  Dosing of autoinjector • Adults 0.3 mg • Pediatrics 0.15 mg  Counseling • Carry two autoinjectors at all times • Optimal dosing not known in obese population  Adequate needle length, dosing concerns EpiPen® Auto-Injectors http://www.epipen.com FDA EpiPen Video: How to Use Delayed Type II: Cytotoxic Reactions  Relatively uncommon  IgG or IgM mediated  Cause host cell destruction through cytotoxic antibodies • Erythrocytes, leukocytes, platelets  Common manifestations • Hemolytic anemia, agranulocytosis, thrombocytopenia  Mechanisms • Hapten-cell reaction • Immune complex reaction  Most commonly associated with high-dose penicillin therapy • Others: quinidine, quinine, cephalosporins, sulfonamides Delayed Type III: Immune Complex-Mediated Reactions  Uncommon  Mediated from formation of antigen-antibody complexes in blood • Complexes form with drug immunogen and antibody in varying ratios • Often deposit in blood vessel walls or tissues  Platelet aggregation, complement activation, or macrophage activation • Results in activation of complement and endothelial cell injury • Local or disseminated inflammatory reactions  Manifestations • Serum sickness • Vasculitis Serum Sickness  Usually occurs1-2 weeks after exposure  Most cases mild and self-limiting  Manifestations • Fever • Malaise • Lymphadenopathy • Cutaneous eruptions (95%) • Joint symptoms (10-50%)  Common medications • PCN’s • Cephalosporins • Ciprofloxacin • Bupropion • Hydantoins • Minocycline • Sulfonamides • Biological agents  Usually self limiting • D/C agent • Can progress to vasculitis  Treat pruritus and arthralgia PRN Hypersensitivity Vasculitis  Immune complex deposition within small veins and arterioles • Activate complement • Release of chemotactic factors • Factors attract polymorphonuclear cells  vessel damage  Inflammation and necrosis of small blood vessel walls  Medications • Allopurinol, β-lactams, sulfonamides, thiazide diuretics, phenytoin, vancomycin Drug-Induced Vasculitis  Accounts for ~10% of all cases of cutaneous vasculitis  Approximately 100 drugs implicated  Diagnosis based on five clinical criteria • • • • • Age >16 Medication at disease onset Slightly elevated purpuric rash Maculopapular rash Granulocytes around an arteriole/venule on biopsy  Manifestations • Palpable purpura, maculopapular rash • May cause multiple organ system involvement • Non-specific inflammatory markers • Onset 7-21 days after therapy initiation  Treatment • D/C offending agent • May use corticosteroids in severe cases Delayed Type IV: Cell-Mediated Reactions  Antigen binds with sensitized T cells • CD4+ or CD8+  Effector mechanism • Recruitment of macrophages, eosinophils or neutrophils  Four subclasses (IVa-IVd)  Clinical manifestations • Contact dermatitis • Bullous exanthems • Maculopapular eruptions • Pustular exanthems Other Allergic Reactions     Not all drug allergies can be described by Coombs and Gell Precise immune drug mechanism may not be known Most common: delayed dermatologic reactions Serious cutaneous adverse drug reactions (SCARs) may be result of immunologic reactions • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) • Mucocutaneous disorders  Stevens-Johnson Syndrome (SJS)  Toxic Epidermal Necrolysis Syndrome (TEN) Mucocutaneous Disorders-SJS and TEN  Purported to result from T-cell response  Keratinocyte apoptosis  Cytotoxic T cells stimulated in response result in apoptosis  Susceptibility • Overexpression of tumor necrosis factor­β, IL­2, and IL­5 seen in skin lesions of some patients with SJS and TEN Stevens-Johnson Syndrome (SJS)  Most common type of severe drug eruption  Manifestations • Typically moderate mucocutaneous and systemic • Blisters, atypical target lesions on <10% of BSA  <10% epidermal detachment • May have more extensive involvement  Difficult to distinguish between TEN  Offending medications: most often longacting sulfonamides • Allopurinol • Carbamazepine • Fluoroquinolones • Hydantoins (phenytoin, fosphenytoin) • Sulfamethoxazole Toxic Epidermal Necrolysis Syndrome (TEN)  Severe, life-threatening mucocutaneous and systemic reaction • May be preceded by prodromal characteristics  Common causes • Infection in pediatrics • HIV+ • Drugs: allopurinol, aminopenicillins, carbamazepine, hydantoins, sulfonamides  Manifestations • Epidermal changes: erythema and massive bullae formations  Bullae easily rupture and peel  >30% epidermal detachment  8 day mortality ~30% Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)  Symptoms/manifestations • High fever • Widespread maculopapular-pustular rash on trunk, arms, and legs  May lead to exfoliative dermatitis, large areas of skin sloughing  Hair and nail loss may occur • Eosinophilia • Late onset internal organ damage • General systemic symptoms e.g. headache and malaise • Secondary bacterial infections may occur • Mortality ~10%  Common offending medications • Sulfonamides • Antimalarials • Anticonvulsants • PCN Management of Type IV Reactions  D/C offending agent  Supportive care • Antihistamines • Topical steroids  SJS/TEN • Severe cases: transfer to burn unit • Systemic corticosteroids controversial • IVIG • Cyclosporine • Anti-TNF therapy Practice A.W. is a 52 year old female who has been receiving high-dose PCN therapy. On day 5 of treatment, A.W. develops jaundice and dark-colored urine. The Coombs test results positive. What type of reaction is A.W. experiencing? a) Type I b) Type II c) Type III d) Type IV Practice B.D. is a 23 year old female who presents to the ED with dyspnea after a bee sting. Physical exam reveals decreased breath sounds and wheezing. VS: BP 97/54 mmHg, HR 120 bpm, RR 22 bpm. PMH: HTN, PCOS. Allergies: bee venom, PCN. What type of reaction is B.D. experiencing? a) Type I b) Type II c) Type III d) Type IV Drug Fever  Febrile reaction to drug without cutaneous symptoms  Occurs in ~10% of inpatients  Difficult to identify • Exclude other causes first  Onset • Median 7-10 days  Pathophysiology • Various mechanisms  Signs/symptoms • Clinical improvement with persistent leukocytosis and/or high-grade fever • Elevated eosinophil count • Skin rash • Bradycardia • Chills • Myalgias • Headache  Treatment • D/C offending agent • May use antipyretics, cooling blankets Drug Fever  Common agents • Antimicrobials  Acyclovir, amphotericin B, B-lactams, minocycline, rifampin, sulfonamides, TCN • Anticonvulsants  Carbamazepine, phenytoin • Antiarrhythmics  Procainamide, quinidine • Cardiac medications  Diltiazem, dobutamine, furosemide, heparin, methyldopa Drug Fever Temperature Pattern  Variable  Four patterns identified • Continuous • Remittent* • Intermittent* • Hectic  102-104 F interrupting normal temperatures throughout the day Drug-Induced Autoimmunity  Certain drugs may induce autoimmune processes • Presence of autoantibodies • May present with clinical features of autoimmune disorder  Medications implicated • Infliximab, etanercept, procainamide, hydralazine, quinidine, isoniazid  Types of autoimmune reactions • • • • Drug-induced hemolytic anemia Interstitial nephritis Drug-induced hepatitis Drug-induced lupus erythematosus (DILE)  Resembles systemic lupus erythematous  Characterized by myalgias, arthralgias, positive ANA titers, elevated ESR Autoimmune Drug Reactions: DILE • Symptoms specific to DILE  Butterfly malar rash  Discoid lesions  Oral mucosal lesions  Raynaud’s phenomenon  Alopecia • DILE associated drugs        Hydralazine Procainamide Isoniazid Chlorpromazine Quinidine Methyldopa Minocycline Respiratory Reactions  Drugs may produce upper or lower respiratory tract reactions • Rhinitis, asthma  May result from direct injury  Asthma may be induced by ASA, NSAIDs, sulfites • Sulfites used in preservatives in foods/medications  Other pulmonary drug reactions • Acute infiltrative and chronic fibrotic pulmonary reactions Insulin  May produce IgE-mediated reaction, immune complex reaction and delayed T-cell mediated allergy  Most common manifestation • IgE-mediated local reaction at injection site  More commonly occurs with beef and pork insulin, less common with recombinant  Systemic reactions rare Other Potential Offending Agents  Pharmaceutical excipients and additives • Not always “inert” • Possible offending agents: benzoyl alcohol, carboxymethylcellulose, povidone, dyes, sodium benzoate, sulfites, polyethoxylated surfactants  Azo dye tartrazine (FD&C Yellow No. 5)  Parabens  Cancer chemotherapy agents Drug Hypersensitivity Reactions (DHRs) DHRs  Clinical signs and symptoms of allergic response • Not proven to be immunologically mediated  Proposed mechanisms • Complement activation • Direct histamine release  Vancomycin Infusion Reaction  Other correlated medications • ASA/NSAIDS • ACE-I/ARB/ARNI • Radiocontrast media • Narcotics • Certain parenteral iron products ASA/NSAIDs  ASA • 2nd most commonly reported allergy • Pseudoallergic reaction • Not consistently associated with IgE • 3 broad categories of reactions  Respiratory  Cutaneous manifestations  Anaphylaxis • COX-1 main contributor ACE-Inhibitors, ARBs, ARNI  Angioedema associated with ACE-I’s • Not dose related • Most commonly occurs within first week of therapy, but may present years later • May be life threatening  Angioedema associated with ARB’s • Much less common vs. ACE-I’s • Most cases involve patients with history of ACE-I induced angioedema  Cough • Pseudoallergic reaction • Can occur in up to 39% of patients after 1 week-6 months • Traditional first line treatments ineffective  Supportive care Radiocontrast Media  Exact cause of reactions unknown • Histamine release, complement activation, direct toxic effects  Classification of reactions •Immediate: within 1 hour  Pruritus, maculopapular drug eruption, SJS, TEN, vasculitis  Risk factors for reaction • Females > males • Asthma • Past reaction to contrast  Pre-treat patients with history  Nausea, flushing, BP changes, bronchospasm, urticaria, angioedema, cardiac arrhythmias, convulsions, angina •Non-immediate: 1 hour – 10 days Image: https://www.healthtap.com/topics/if-you-are-allergic-to-shellfish-can-you-take-pills-with-iodine Narcotic Analgesics  Certain opiates stimulate histamine release • Hypotension, tachycardia, facial flushing, diaphoresis, or pruritus • Severe reactions uncommon • May administer with antihistamine Iron-Dextran Injection  Ferric hydroxide (InFeD) or ferric oxyhydroxide (DexFerrum) • Complexed with low molecular weight dextran  Hypersensitivity reactions • Not dose related • May occur with first drug exposure • Consistent with non-immunologic mechanism  Adverse events • Chest pain • Hypo/hyper tension • Abdominal pain, N&V • Weakness • Syncope • Backache • Arthralgias, myalgias • Hypersensitivity reactions  Urticaria, sweating, dyspnea, rash, fever, anaphylactoid reactions Practice Case L.M. is a 61 year old male recently admitted to the hospital with a diagnosis of CAP, with the causative organism identified by urine antigen testing: Streptococcus pneumoniae. L.M. was successfully treated with ceftriaxone and discharged 5 days later. L.M. presented to the urgent care clinic 5 days after discharge with joint pain and cutaneous eruptions. Temp: 100.9 F. What type of reaction is L.M. experiencing? How can L.M.’s reaction be managed? Pharmacist Role Drug History and Documentation Penicillin Skin Testing Desensitization Protocol Investigation of Detailed Drug History  Medication name  Route administered  Prescribing indication  Type and severity of reaction  Prior allergy history  Date of reaction  Family history of similar reactions  Prior exposure to same or structurally related medications  Concurrent medications  Reaction management  Treatment response  Prior diagnostic testing or rechallenge  Other medical problems Penicillin Skin Testing  Penicilloyl polylysine (PPL) [Pre-Pen] • Identifies 80% of PCN allergic patients • IgE antibody specific identification  Determinants of true allergy • PPL: major determinant • Penicillin G: minor determinant See article: Jones BM, Bland CM. Penicillin skin testing as an antimicrobial stewardship initiative. Am J Health Syst Pharm. 2017;74:232–237. Penicillin Skin Testing Agent PPL [Pre-Pen] Major determinant PPL Procedure Puncture (scratch) test one drop of full-strength solution (6 x 10-5 mol/L) Interpretation No wheal or erythema or wheal <5 mm diameter after 15 minutes: proceed with intradermal test Wheal or erythema >5-15 mm diameter within 15 minutes: choose alternative agent, consider desensitization if no other alternatives exist Intradermal test: inject PPL to raise intradermal bleb 3 mm diameter Saline: negative control Histamine: positive control (optional) Read at 20 min: negative response = no increase in size of original bleb, no greater than reaction at control site Penicillin G potassium (>1 week old) Scratch test one drop of 10,000 unit/mL solution Same as scratch test with PPL (see above) Penicillin G potassium Intradermal test: 0.002 mL of 10,000 unit/mL solution Serial testing can be performed Same as intradermal test with PPL (see above) Positive response = itching & increase in size of original bleb >5 mm and > than saline control  choose alternative agent, consider desensitization Allergic Reactions Stephen H. McCall, PharmD, BCPS, BCCCP | [email protected] Assistant Professor of Pharmacy Practice PHA 5373|IS X – Critical Care July 19th, 2023