Oct 17, 2011

III-IIb
HYPERSENSITIVITY REACTION
Dr. Edquilag

ALLERGY Coined in 1906 by the Viennese pediatrician Clemens von Pirquet Abnormal immune response to a substance ( allergen) that would otherwise be harmless

HYPERSENSITIVITY REACTIONS

Allergenthe antigens that give rise to immediate hypersensitivity Atopythe genetic predisposition to synthesize inappropriate levels of IgE specific for external allergens increased tendency toward type I hypersensitivity (IgE allergies) HOST and ENVIRONMENTAL FACTIORS IN DEVELOPMENT OF ALLERGIC RESPONSE Cytokine dysregulation TH2 Phenotype ( proallergy) Genes Environment TYPE 1 IgE mediated Present in atopic individuals; Directed to specific antigen only Occur within minutes of exposure to antigen Antigens combine with IgE antibodies IgE binds to mast cells and basophils, causing them to undergo degranulation and release several mediators: Histamine: Dilates and increases permeability of blood vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion. Leukotrienes: Bronchial spasms mast cells / basophils are major effectors o have high-affinity Fc receptors for IgE o granules contain mediators of HS-I reaction .ALLERGIC RESPONSE

hygiene hypothesis of allergy induction contends that too clean of an environment and lack of infections during childhood (along with a genetic susceptibility) promote a bias of the immune system toward TH2 and IgE

Gell and Coombs Types of Hypersensitivity Reaction Mediator Mechanism I Anaphylactic IgE Histamine II Cytotoxic IgM, IgG Antibody Cell surface antigen (opsonized) *Antibody dependent cell mediated cytotoxicity (ADCC) Complement mediated, recruitment and activation of leukocytes 1) Macrophage activation 2) Direct target cell

Examples Asthma, anaphylaxis ABO, drug induced reaction

III Immune Complex

IgG

Serum sickness, arthus reaction

Within minutes Mast cell degranulation Histamine Leukotrienes Proteases

IV Delayed Type Hypersensitivity

CD4 and CD8

Contact dermatitis, GVHD, PPD Test

Immediate hypersensitivity reaction

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Hours -

Cytokines Chemokines

Signs and Symptoms CUTANEOUS Urticaria, angioedema Flushing Pruritus without rash RESPIRATORY DIZZINESS, SYNCOPE C. LABORATORY TESTS

>90% -

85-90% 45-35% 40-60 30-35%

Late Phase Reaction ( can no longer be addressed by histamine)

TESTS Serum Tryptase

chemokines- subsatnce released by inflammatory cells Bronchus- constriction Eyes- conjunctivitis Skin- urticaria epidermis Angioedema- deeper layer of skin ( involves the SQ) Allergic Rhinitis- nasal congestion ( allergic salute- may demo pa c doc nito , allergic shiner and rabbit nose) ANAPHYLAXIS Severe, potentially fatal, systemic allergy IgE mediated May occur suddenly INCIDENCE: underreported 50-2,000 per 100,000 ALLERGEN Food 59% Peanut -12% Treenut ( walnut, cashew, pistachio) -12% Cows milk -8% Fish -8% Eggs -4% Others -15% Insect sting 13% Specific Immunotherapy 12% Medications 6% Others 4% Unknown 95 ** peanut allergy is an important cause of food-induced anaphylaxis accounting for the majority of fatal and near-fatal reactions ( sosyal ka daw pag may peanut allergy ka) ** Phils- seafoods A. PATHOGENESIS Principal pathologic features in fatal anaphylaxis include acute pulmonary hyperinflation, pulmonary edema, intra-alveolar hemorrhaging, visceral congestion, laryngeal edema, and urticaria and angioedema. Acute hypotension is attributed to vasomotor dilation and/or cardiac dysrhythmias. Initial exposure reexposure causes severe reaction B. CLINICAL MANIFESTATIONS onset of symptoms vary depending on the cause of the reaction Reactions from ingested allergens (foods, medications) are delayed in onset (minutes to 2 hr) compared with injected allergens (insect sting, medications) and tend to have more gastrointestinal symptoms.

Plasma Histamine 24 hour urinary histamine (metaboilte: methylhistamine) D.

Peak 60-90 minutes after onset of anaphylaxis Persists to 6 hours Measurement obtained b/w 1-2 hrs Levels begin to rise within 5-10 mins, remain increased only for 30-60 minutes Increased for longer period of time up to 4 hours ( un nga lang..accdg to doc man, wala sa pinas to!)

TREATMENT Anaphylaxis is a medical emergency requiring aggressive management Airway, Breathing and Circulation Epinephrine ( some anaphylaxis can go on for days)

EPINEPHRINE Primary and most important treatment Delay in administration risk factor for death Airway obstruction most common cause of death DOSE Adult Pedia 0.5 ml ( 1:1000) in 5-20 min 0.01 mg/kg ( 0.3ml max)

WHEN TO GIVE: ASAP!!! IM ( anterior thigh) Epi pen not available sa PINAS (again!) costs about $150 ** Aqueous epi is the available form

Second-Line of Treatment Anti-Histamine cetirizine, diphenhydramine Steroids E. PREVENTION of TREATMENT Allergy Evaluation Education Avoidance EpiPen Medic alert bracelet Skin test and Desensitization Test (for drug allergy)

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TYPE 2 Cytotxic Cytotxic, IgG mediated antibodies directed against target antigens on the surface of cells or other tissue components Involve activation of complement by IgG or IgM binding to an antigenic cell. Abs vs. cell surface Ags C lysis(MAC) or ADCC ( antibody dependent cell mediated cytotoxicity Antigenic cell is lysed. Example Transfusion reactions: ABO Blood group system: Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream. ABO Blood Type A B O AB

Examples Systemic Lupus erythematosus ( systemic joints, nephritis) Poststreptococcal glomerulonephritis ( nephritis) Goospadtures syndrome ( lungs) Serum Sickness ( vasculitis, nephritis) Arthus Reaction ( cutaneous vasculitis) SERUM SICKNESS Von Priquet and and Schick in 1905 first described the disorder in children treated with horse serum Systemic, Symptoms ensue from the activation of complement by antigenantibody complexes and other reactions ( mast cells)

Ag A yes no no yes

Ag B no yes no yes

Antibody Antibody anti-A Anti-B no yes yes no yes no yes no A. Clinical Manifestations Begins 7-12 days after injection of foreign material clinical features such as fever,malaise, rashes urticaria, arthralgias, lymph node enlargement, and proteinuria appear self-limited recovery within 1-2 weeks Rare complications: carditis, glomerulonephritis, GBS Diagnosis: Good clinical history Decrease C3 and C4 Immune deposits of IgM,IgA, IgE or C3 Treatment Discontinuation of offending agent Anti-histamine and Supportive tx

Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta o Rh Blood Group System: 85% of population is Rh positive. o Rh negative mom with Rh+ fetus makes Abs vs baby rbc that enter mom circ. at birth o next pregnancy: IgG Abs cross placenta, destroy fetal rbc jaundice, brain damage Autoimmune hemolytic anemia and type II drug reaction autoAbs can result from drugs (e.g., penicillin) that stick to rbc Abs C activation

B.

TYPE 3 Immune complex immune complexes formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation. The antigens may be exogenous -microbial proteins, or endogenous as nucleoproteins. when these complexes are produced in large amounts, persist, and are deposited in tissues they then became pathogenic. Immune complex-mediated injury is systemic when complexes are formed in the circulation and are deposited in several organs, or localized to particular organs (e.g., kidneys, joints, or skin) if the complexes are formed and deposited in a specific site. Antibody-Antigen immune complexes are deposited in organs, activate complement, and cause inflammatory damage. Glomerulonephritis: Inflammatory kidney damage.

C.

TYPE 4 Delayed Type Hypersensitivity A. antibody-independent mechanisms involving sensitized T cells and cytokines. Reactions are delayed by one or more days (delayed type hypersensitivity). Delay is due to migration of macrophages and T cells to site of foreign antigens. Reactions are frequently displayed on the skin: itching, redness, swelling, pain.

MECHANISM CD4 t cells response to antigen secreting cytokines Examples: PPD test Contact dermatitis Graft versus Host Disease (GVHD)

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GRAFT VERSUS HOST DISEASE Graft contains immunocompetent cells Host must be immunocompromised and unable to reject or mount a response to graft Must be histocompatibility difference between graft and host HIGH RISK for GVHD Allogeneic & autologous hematopoietic cell transplantation (age, HLA disparity, gender disparity, allosensitized donor) Solid organ transplantation (liver, small bowel) Transfusion of unirradiated blood products (fetuses, neonates, immunodeficiency syndromes, chemoradiotherapy A. 1. CLASSIFICATION of GVHD ACUTE Occurring <100 days post transplant Foreign protein, CD4 release cytokines activate CD8 cytotoxic and NK cells

PREVENTION: Prophylaxis with Immunosuppressive agents Selective depletion of alloreactive T lymphocytes from the donor graft ( depletion of T cells) before transplant Choosing more closely HLA-matched donor SYMPTOMS: Triad of dermatitis ( erythroderma) , hepatitis ( cholestatic) and enteritis 2. CHRONIC >100d after transplant Diverse range of affected organ systems 70-90% evolve from acute GVHD Alloreactive donor T cells to host cells Recurrent infection 24% HLA matched with SCT( stem cell transplant) 37% match unrelated to SCT B. THERAPY: Prednisone and Cyclosporine

Poor OUTCOME: External skin infection Thrombocytopenia Progression after dx

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