Hypersensitivities, Autoimmune & Immunocompromised Disorders

Hypersensitivities, Autoimmune and Immunocompromised Disordersv    HypersensitivityØ     Classified I-IV by:§       Source of antigen: Environmental, acquired, etc§       Time sequence:       Immediate vs. delayed§       Basic immunologic mechanism causing the injury·       Histamine release, etc.Ø     Causes§       Foods:        Chocolate, eggs, wheat, milk, nuts, seafood (iodine), strawberries§       Medications:                        Antibiotics (Major Offender)§       Dyes in diagnostic tests:       Iodine/Barium §       Animals/pets§       Venoms                              Bees, hornets, wasps, spiders§       Inhalants:                            Allergies, Pollens, dust, cigarette smoke, pollutants    §       Serums: from animals:         Horse serum used in antitoxins§       Contactants:                       Tape, cosmetics§       Intrinsic:                             Bacteria: (G-) →shockv    Types of Hypersensitivity ReactionsØ     Type I- IgE mediated§       Exposure to antigen §       Bind with Mast cells—severe inflammation§       Histamine release—↑ permeability  §       Autonomic nervous system—Controls BP & constriction  §       Genetic predisposition—atopic §       Life threatening—anaphylaxis only§       Desensitization—allergy shotsØ     Type II- Tissue Specific§       Involves tissues and organs§       Antigen reacts with antibody on cell wall§       Antigen-antibody complexes form§       Destruction by:·       Activation of complement cascade resulting in cytolysis·       Enhanced phagocytosis·       Cytoxic T-cell interaction: b/c it thinks it will fight·       Malfunction of cell: if it doesn’t die§       Transfusion Reaction—within 15 minutes. ·       Symptoms:¨     Chills, N/V, Fever, Low back pain from kidneys!       ¨     Hypotension, Tachycardia    ¨     Shock, Anxiety                    ¨     Hyperkalemia         Ø     Type III§       2^ndary to antigen-antibody complexes§       Complexes deposited in tissues/blood vessels/joints→ tissue damage §       Local or systemic§       Immediate or delayed§       Common sites: kidneys, skin, joints§       Examples: SLE, RAØ     Type IV- T-Cell mediated!§       Delayed Hypersensitivity: Start S&S in 24 hrs, but can be months/years.§       T-cells – toxin killing mechanism·       Attack and destroy cells/multiply ·       Recruit phagocytic cellsØ     Example: tissue graft rejection, tuberculin reaction, allergic reactions—delayed and topical. Ex: Poison Ivy.  Usually localized. v    Autoimmune DisordersØ     SystemicØ     Tissue specificØ     Genetic susceptibilityØ     Environmental factors Ø     Systemic Lupus Erythematosus (SLE)§       Chronic§       Inflammatory§       Deposition of immune complexes: Type III Hypersensitivity §       Etiology·       Genetic: Women age 18-40, Blacks, and twins ·       Environmental·       Autoantibodies: against own tissues ·       Anti-nuclear antibodies (ANA)·       Anti-DNA antibodies·       Affect blood cells§       Clinical manifestations·       Facial rash—butterfly rash.  ·       Renal problems—inflammation damages kidneys ·       Arthritis·       Presence of ANA·       Hematological disorders: ↓ WBC/RBC & platelets.§       Diagnosis·       History: Occupation, exposures as child·       PE·       Serum analysis: Anti-DNA antibody most specific §       Treatment:  All treat symptoms b/c no cure!·       NSAIDS—                                Pain & inflammation ·       Antimalarial medication—         Plaquenil ·       Corticosteroids—                     Anti-inflammatory ·       Immunosuppresive Medsv    Host-Verses-Graft RejectionØ     Pathophysiology§       HLA antigens§       Type IV reaction                 T-cells!§       Hyperacute rejection—      Immediate §       Acute rejection—               days→months.  Antibodies against HLA antigen§       Chronic rejection—            months→years. Weak Type 4 reactionv    Graft-Versus-Host Disease:   Graft is rejecting YOU!Ø     Pathophysiology§       Immunocompromised transplantation—common w/ bone marrow transplant§       GVHD development·       Functional cellular immune component—from T-cells·       Foreign antigens·       Immunocompromised recipient§       Acute§       Chronicv    ImmunodeficienciesØ     Congenital=inherited & often opportunistic §       Abnormalities in cell maturation§       Hypogammaglobulinemia—↓ antibodies in blood §       Severe combined immunodeficiencies (SCIDs)·       Cell mediated T-cells & antibody (plasma B-cells)§       Adenosine deaminase deficiency (ADA)·       Lacks enzyme so toxins buildup.  Causes lymphocytes to not mature properly §       Purine nucleoside phosphorylase deficiency (PNP)Ø     DeGeorge Syndrome§       T-Cell deficiency§       Defect on chromosome 22§       Clinical manifestations·       Facial disorders·       Low set and angulated ears·       Hypocalcemia·       Chronic infections§       Treatment·       Thymus transplant·       Bone marrow transplantØ     Selective Immunoglobulin A Deficiency§       Affects mature B cells·       Genetic·       Environmental§       Symptoms·       Asymptomatic·       URI’s·       Allergic manifestations§       Treatment·       NoneØ     Acquired§       Nutritional§       Iatrogenic§       Trauma§       Stressv    AIDSØ     HIV§       Retrovirus§       RNA§       Reverse transcriptase§       Double stranded DNA§       New genetic make-up§       Viremia§       Low HIV levels – 10 to 12 years (poss)·       Replicating at fast rate§       HIV looking for CD4 receptors·       Lymphocytes·       Monocytes/macrophages·       Astrocytes·       Oligodendrocytes §       T cells have more CD4 receptors·       Unfortunate: T- cells play a key role in the immune system’s ability to recognize and defend itself against pathogens·       Normal CD-4 level is 800 – 1200 cells/microliter·       Normal life span = 100 days; HIV = 2 days·       Destroys 1 billion CD4 T cells every day·       Healthy immune system = CD4 T at 500 cells/microliter·       CD4 T= 200-499 – immune problems·       CD4 T= < 200 – opportunistic infectionsØ     Transmission of HIV§       Blood§       Semen and Vaginal fluid§       Breast milk§       Saliva§       Tears§       Sweat§       InsectsØ     Variables for Transmission§       Duration & frequency of contact§       Volume of fluid§       Virulence & concentration of the organism§       Host immune statusØ     Primary Infection Phase§       High viral load§       Dramatic drop in CD4 cell counts§       Flu-like symptoms§       Window period§       Antibodies develop (usually can be detected in 4-12 weeks) Ø     Latency Phase: Initial§       Asymptomatic phase§       Vague symptoms§       CD4 T count > 500 cells/microliter§       High risk à even though no symptoms, can still transmit HIV to othersØ     Latency Phase: Intermediate§       Asymptomatic but virus is replicating§       May have recurrent infections of sinuses/respiratory tract, ^ fatigue§       CD4 T counts continue to fall – between 200-500§       Damage to lymphatic structures à loose ability to  contain destructive HIVØ     Latency Phase: Late§       Continued decrease of CD-4 Cells§       Occurrence of opportunistic infections·       Oropharyngeal candidal infection·       Shingles·       P. carinii pneumonia·       Oral/genital herpes·       Kaposi Sarcoma·       Oral hairy leukoplakiaØ     Overt AIDS Phase§       Diagnosis of AIDS (Acquired Immunodeficiency Syndrome)§       Immune system becomes severely compromised§       CDC Diagnostic criteria for AIDS= HIV positive§       At least one of: ·       CD4+ below 200/ul.·       Opportunistic infection·       Development of opportunistic cancer·       Wasting syndrome occurs (loss of 10% ideal body mass)·       Dementia Ø     Diagnosis§       HIV antibody test (ELISA)§       Western Blot Assay§       PCR§       OraSure test§       Ora Quick Rapid HIV-1 Antibody TestØ     Treatment§       NO CURE§       Anti-Retroviral medication= HAART§       Drugs§       Antibiotics§       Antifungals§       Vaccines§       Influenza§       Pneumonia 

HIV and Immune System Pharmacology

HIV and Immune System Pharmacologyv    MOAØ     Nucleoside Reverse Transcriptinase Inhibitors (NRTI’s) §       Mimics neucleocides needed to convert RNA→DNA & Inhibits enzyme Ø     NonNucleoside Reverse Transcriptinase Inhibitors (NNRTI’s)§       Binds near active site to inactivates reverse transcriptase enzymeØ     Protease Inhibitors (PI’s)§       Inhibit protease enzyme needed from DNA at tail end of process.  §       Prevents new RNA virus from splitting Ø     Fusion Inhibitors§       Targets 1^st step w/ fusion & initial entry w/ cell§       Tie up CD4 receptor site so virus can’t latch on§       Last-ditch effort v    Therapy recommendationsØ     Single-Drug: IneffectiveØ     HAART: Highly Active Antiretrovial Therapy§       Combinations of RT’s and PI’s into nice cocktailv    IndicationsØ     Active HIVv    ContraindicationsØ     Severe allergy: weigh pros/consØ     Intolerable toxicity:  N/V, diarrhea, rash, pancreatitis, liver/kidney toxicity, bone marrow depression, hepatitis patients v    Side Effects/Adverse EffectsØ     Same and nonretroviral: nausea, vomiting, diarheaØ     Tolerate: Strict drug schedule.Ø     Myalgias/ joint painv    Drug interactionsØ     MULTIPLE!!  Look up!v    Specific AgentsØ     NRTI’s: §       Zidovudine (AZT, Retrovir): ·       Newborns with HIV mom  ·       Post-exposure prophylaxis§       Lamivudine (Epivir): ·       Rapid PO absorption. ·       Bactrim ↑ level to toxicicity.  §       Tenovir (Viread): ·       ↓ effecacy of PI’s Ø     NNRTI’s: Great PO & heavily metabolized by cytochrome P450 system §       Delavirdine (Rescriptor): ·       Nasty rash §       Efavirenz (Sustiva): ·       Psychiatric problems §       Nevirapine (Viramune):·       Stevens-Johnson Syndrome·       No women with CD4 count ↓ 200- hepatotoxicity risk Ø     Protease Inhibitors (PI’s): ∆ fat distribution, ↑ cholesterol & blood sugars§       Amprenavir (Agenerase):           Take w/ fatty meal§       Nelfinavir (Viracept):       Take w/ fatty meal§       Indinavir (Crixivan):        Kidney stones. Combo w/ 2 retrovirals. §       Lopinavir/ritonavir (Kaletra):      Ritonavir ↓ metabolism of lopinavir  Ø     Fusion Inhibitors: §       Enfuvirtide (Fuzeon):       Limited usage—last efforts v    Immunosuppressant AgentsØ     MOA:§       Varies§       Suppress certain T lymphocyte cells w/ cellular immunity Ø     Indications§       Organ rejection prevention§       SLE-lupus§       RA§       Psoriasis§       IBS§       Crones Disease Ø     Contraindications§       Allergy§       Relative·       Renal/hepatic failure·       Pregnancy & teratogens Ø     Side Effects/Adverse Effects§       Susceptibility to infection§       Hepatotoxcitity!Ø     Interactions§       Cyclosporine has many·       Cardiovascular meds:                      ↑ cyclosporine level ·       Cytochrome P-450 system ·       Nephrotoxic agents·       HIV agents ·       Anti-infectives:                    ↑ cyclosporine levelsØ     Specific Agents§       Cyclosporine (Neoral)·       Post-transplant ·       RA & psoriasis §       Azathioprine (Imuran)·       ↓ B & T cell production ·       Severe RA & kidney transplant§       Basiliximab (Simulect)·       Interleukin 2 antagonist w/ complement cascade·       Perioperative care w/ kidney transplants§       Sirolimus (Rapamune)·       ↓ T-cell function·       Combo w/ steriods/Cyclosporin for kidney transplants§       Mycophnolate mofetil (CellCept)·       ↓ B & T cells·       Renal/Heart transplants·       Combo w/ steroids/Cyclosporin§       Tacrolimus (Prograf)·       Inhibits T-cell activation·       Liver/Kidney transplants…↑ Nephrotoxicity w/ Cyclosporin Ø     Special Considerations§       Contact with others §       Pregnancy§       Leukocyte count- ↓ 3,000 dangerous§       RBC counts§       Children§       Co-morbidities v    Immunizing AgentsØ     Toxoids§       Inactivated bacterial toxins§       Usually enough to stimulate antibody response§       Immunity may not be lifelong b/c toxoid inactivatedØ     Vaccines§       Usually lifelong§       Not as strong as live vaccine, may require boosters§       Live vaccines usually attenuated (weakened) of bacteria/virus which sets off immune system.  Can have lifelong immunity. Ø     Immunoglobulin Therapy§       Passive immunity where we give you antibodies to help pt fight.  v    MOA: Ø     Immune responseØ     Active: Vaccines and toxoidsØ     Passive: Immunoglobulins: need quick antibodiesv    IndicationsØ     ImmunityØ     Temporary protectionv    ContraindicationsØ     Allergies§       Toxin§       Synthetic components: Many ppl allergic to synthetic components and not toxoid itself. Ex: egg product/horsesØ     Febrile illness§       Important for kids b/c many immunizations when children.  Immune system already busy.  Kids that are febrile PRIOR to getting med.Ø     Immunocompromised state§       Don’t give any LIVE vaccine to thesev    Side EffectsØ     Fever AFTER immunization§       Soreness at injection site§       Expect to go away after few daysv    Adverse EffectsØ     Serum Sickness: Caused by equine vaccines/toxins that causes laryngeal swelling/tongue and facial edema, and rash v    Special PopulationsØ     Preterm infants- (if child born 2 weeks premature and is 4 wks old, really only 2 weeks old.)  Immunize based on REAL birthday. Ø     Pregnancy:  Never give live vaccines. After 1^st trimester if necessary.Ø     Limited Immunodeficient: Not immunocompromized but immunodificient. ARE able to receive vaccines. Ø     Active disease: Want to give toxoids (=killed bacteria)/killed vaccines /immunoglobulins.  v    Specific Agents (active)Ø     Haemophilus influenzae (Hib)§       Only vaccinate for kids under 5§       Cause meningitis, epiglotitis Ø     Hepatitis B (Recombivax)§       What we get.  Get boosters.  Ø     Influenza (FluShield)§       Live immunizationØ     Measles, mumps, rubella (MMR II)§       Viral illnesses.  Have boosters§       Not recommended/contraindicated w/ pregnant womemØ     Diptheria, tetanus, and pertussis (DTaP)§       Both Toxoids.  Pertussis is inactivated, but back in gear.  Ø     Pneumococcal (Pneumovax)§       Fights pneumococcal pnemonia, but other pneumococcal.  Don’t call “pnemonia vaccine” b/c fights other stuff.  Given to those over age 65 and few kids. 23 strains.Ø     Polio (IPV)§       Completely inactivated b/c very dangerousØ     Varicella (Varivax)§       Live; childhood immunization.  Pts older than 13 and never been exposed to chickenpox or vaccinated, may give this.  Ø     Meningococcal (Menomune)§       Ppl in dorms.Ø     Rabies (Imovax)§       Kills quickly.  If body can’t fight, die in 3 days.§       Only get it if you’ve had risk for exposure.  Ø     HPV (Gardasil)§       Very common. STD ONLY!!  Protect with strains that lead to cervical cancer. Men always asymtomatic.  Given w/ ages 9-26.  v    Passive: (many times combo w/ active)Ø     Hepatitis B immune globulin (H-BIG2)Ø     Immune globulin (Gammagard)§       Just IgG that’s powerful with fighting infection.Ø     Rabies immune globulin (RIG)Ø     Tetanus immune globulin (Hyper-Tet)Ø     Varicella zoster immune globulin (VZIG)