Chapter 7 - Pharmacology and Therapeutics

Question 1

What are some other rare adverse effects of IVIG

What are some pretreatment options for mild IVIG reactions

Answer 1

• thrombotic events, stroke, MI, hemolytic anemia, TRALI
• aspirin, tylenol, Benadryl, hydrocortisone, slow infusion rate
• for serious IVIG reactions, or history, have epi available

Question 2

How does IgG Fc Receptor Blockade work

Answer 2

inhibits antibody-dependent cell-mediated cytoxocity (ADCC) by blockade of FcgammaRIII (CD16) (remember, this is the NK cell receptor)

inhibits antibody production by blocking FcgammaRIIb (CD32) on B lymphocytes

in ITP, IVIG generally blocks membrane Fc receptors on phagocytes in the spleen and liver

Question 3

Silver Vial

Answer 3

1:10,000

Question 4

What are three conditions for which IgG replacement should NOT be used

Answer 4

sIgA deficiency

IgG due to protein loss

IgG subclass deficiency

transient hypogam of infancy

Question 5

In the IVIG manufacturing process, what does filtration do

Answer 5

filtration removes antibody aggregates and viruses

Question 6

What changes in cytokine profile occur with AIT

Answer 6

shift from Th2 (IL-4, IL-5, IL-13) to Th1 (IFN-gamma, IL-12)

increase in Th1/Th2 ratio
increase in IFN-gamma/IL-4 ratio

Question 7

what are contraindications to SLIT

Answer 7

severe asthma and eosinophilic esophagitis

Question 8

What does IVIG contain

Answer 8

Mostly monomeric IgG (>95%) and small amounts of IgA and IgM

Question 9

What forms of IgG replacement are available

Answer 9

generally IV, IM, SC. SCIG has fewer side effects and is an infusion at home. Benefits are stable trough levels and fewer side effects

Question 10

in the IVIG manufacturing process, what does stabilization do

Answer 10

this helps prevent aggregation of Ig molecules

different chemicals are used (albumin, glycine, etc). low pH helps to get rid of aggregates but also minimize damage to the therapeutic activity of the Ig

Question 11

Review nomenclature for labelling AIT vials

Answer 11

Question 12

In the IVIG manufacturing process, what does viral inactivation do

Answer 12

enveloped viruses can be inactivated by chemical methods (solvent/detergent, low pH)

physical methods are required for nonenveloped viruses (pasteurization, column chromatography, nanofiltration)

Question 13

what is the effective maintenance dose for most inhalant allergens

Answer 13

between 5 and 20 micrograms per 0.5ml maintenance dose

Question 14

What is the efficacy of AIT on asthma

Answer 14

Symptom scores improve and medication use decreases

decreases bronchial hyperreactivity but does NOT affect PFTs

particularly in children, AIT can help prevent allergic asthma

Question 15

Green Vial

Answer 15

1:1000

Question 16

What type of immune cells increase in AIT

Answer 16

CD4+CD25+ Treg cells (IL-10, TGF-beta)

CD8 cells

Question 17

Why do some SCIG products come with hyaluronidase

Answer 17

ithis is because it is difficult to give large amounts of Ig by the subcutaneous route unless pretreated with hyaluronidase, which improves permeability

Question 18

What are the FDA-approved indications for IVIG (8)

Answer 18

1. primary immunodeficiencies 2. CLL 3. Kawasaki disease 4. following stem cell transplant with B-lymphocyte non-engraftment 5. pediatric HIV infection (recurrent bacterial infections) 6. ITP 7. CIDP 8. bone marrow transplant

Question 19

What stabilizer in IVIG is associated with acute renal failure

Answer 19

Sucrose

Question 20

How is Ig isolated from plasma in the manufacturing process

Answer 20

Broadly speaking, ethanol is used to fractionate the pooled plasma.

Usually, the modified Cohn-Oncley cold ethanol fractionation method is used. This step also gets rid of prion particles

Question 21

What are some specific hyperimmune globulins that people prescribe to patients (7)

Answer 21

globulins from people who have high titers to a desired antibody, either naturally acquired or stimulated by immunization. They are used to transfer passive immunity for postexposure prophylaxis

examples are to hepatitis B, rabies, tetanus, varicella-zoster, vaccinia, CMV, and RSV

Question 22

What are some key facts about aseptic meningitis with IVIG

Answer 22

history of migraine is a predisposing factor

associated with large doses, rapid infusions, and the treatment of patients with autoimmune/inflammatory disorders

Question 23

What are the age considerations in AIT

Answer 23

There are no upper or lower age limits, but children should be able to communicate effectively and comorbidities in the elderly should be considered

Question 24

Red Vial

Answer 24

1:1 (maintenance concentrate)

Question 25

Review cross-reactivity patterns of allergen extracts

Answer 25

Question 26

Review SLIT

Answer 26

5 grass SLIT - Oralair Timothy Grass - Grastek Ragweed - Ragwitek dust mite - Odactra local reactions common but pretty effective

Question 27

what extracts are safe to mix with high-protease extracts

Answer 27

ragweed and cat (in 50% glycerin)

Question 28

T/F Local reactions are common to AIT

Answer 28

redness or swelling dime to quarter size is common and do not predict systemics. frequent large local reactions (\>25 mm) may predict systemics

Question 29

Approximately how many donors contribute to one dose of IVIG

Answer 29

15,000-60,000

Question 30

What is the typical period of maintenance immunotherapy?

Answer 30

3-5 years

Question 31

What is the serum half life of IVIG

Answer 31

3-4 weeks

Question 32

Systemic reactions are rare - how rare? what increases the risk?

Answer 32

0.2%, normally within 30 minutes taking beta blockers increases risk

Question 33

What is the standard starting dose of IVIG

Answer 33

400-600 mg/kg every 3-4 weeks

Question 34

Review "Uses of Immunoglobulin Therapy"

Answer 34

Question 35

Blue Vial

Answer 35

1:100

Question 36

What are relative contraindications to AIT

Answer 36

pregnancy (ok for maintenance, not buildup) serious immunodeficiency malignancy poorly controlled or severe asthma significant CV disease caution with beta blockers (AIT) and ACEI (VIT)

Question 37

Which extracts degrade pollen

Answer 37

Mold and cockroach

Question 38

What things decrease in AIT

Answer 38

seasonal rise in allergen-specific IgE low affinity IgE receptor (FcERII/CD23) basophil hyperreactivity recruitment of basophils, eos, and mast cells in nose/lung allergen-specific lymphocyte proliferation

Question 39

Yellow Vial

Answer 39

1:10

Question 40

monoclonal antibody against epidermal growth factor receptor

Answer 40

Cetuximab - used in the treatment of some colorectal and head/neck cancers. has a novel mechanism of anaphylaxis that can be predicted by the presence of IgE antibodies against naturally occuring galactose-alpha-1,3-galactose (oligosaccharides related to the ABO blood group) even before exposure to the drug. these pre-existing IgE antibodies appear to put patients at risk for anaphylaxis to this drug

Question 41

What is AIT an effective treatment for (**4**)

Answer 41

Allergic Rhinitis/Conjunctivitis Allergic Asthma Atopic Dermatitis with Aeroallergen Sensitization (dust mites) Stinging-Insect Hypersensitivity

Question 42

It is ok to mix dust mite (\>=10% glycerin) with what extracts

Answer 42

pollen, dog, cat, cockroach, mold extracts

Question 43

What vaccines have diminished immunogenicity after IVIG

Answer 43

Live virus vaccines don't work as well when given shortly before or during several months after receipt of Ig products.

Question 44

Besides Fc Receptor blockade and sialyated IgG fraction mediation, by what other mechanisms (3) does does IgG therapy have immunosuppresive effects

Answer 44

neutralization of autoantibodies, toxins, superantigens inhibition of of cytokine production inhibition of complement uptake/elimination of immune complexes

Question 45

T/F Glycerin is associated with local reactions

Answer 45

F however, it can be irritating and painful

Question 46

What is the standard starting dose for SCIG

Answer 46

100mg/kg/week

Question 47

How safe is IVIG

Answer 47

viral and prion elimination is considered to be safe no transmission of any infectious diseases has occurred since the mid-1990s

Question 48

list all the things that increase risk of systemics in AIT

Answer 48

beta blockers unstable asthma history of previous systemics during "priming" of pollen season during buildup during accelerated or rushed protocols first injection from new vial dosing error

Question 49

What antibodies increase when AIT is started

Answer 49

IgG blocking antibody (initially IgG1 and IgG2 --\> IgG4) IgA IgE (initially, in the first few months, but ultimately decreases over years)

Question 50

How does the sialyated IgG fraction in IgG mediate immunosuppressive activity

Answer 50

terminal alpha-2-6 linked sialic acid residue on the N-linked glycans of the IgG Fc domain have been shown to be immunosuppressive

Question 51

Which venoms can you mix together

Answer 51

venoms contain proteases and should not be mixed, except for vespid venoms (hornets/yellow jackets)

Question 52

What are some **mild reactions** to IVIG administration

Answer 52

headache, fatigue, fever, chills, nausea, vomiting, myalgias (flu-like symptoms) usually rate-dependent, occur during initial doses, and improve over time

Question 53

bonus question - What is the standard dose required for immunomodulation (as opposed to replacement)? IE, for patients with something like Kawasaki disease

Answer 53

in this case, higher doses are needed (2g/kg)

Question 54

What's the issue with IgA deficiency and IgG replacement

Answer 54

some people with IgA deficiency have anti-IgA antibodies, thus can have problems when they receive this blood product. There are products containing low IgA

Question 55

Why are patients with sIgA deficiency predisposed to anaphylaxis with IVIG and other blood products

Answer 55

sometimes they have antibodies to IgA. one strategy is to use products with low IgA content, or pretreat with antihistamines and corticosteroids

Question 56

what are major (1) and minor determinants (3) for penicillin

Answer 56

**major** benzylpenicilloyl polylysine (Pre-Pen) **minor** penicillin G, penicilloate, penilloate (if available) most PCN allergy (80%) is related to major determinant

Question 57

what do you do if a patient has a reaction during desensitization? what are contraindications?

Answer 57

repeat/decrease dose, treat, keep going contraindications include TEN, DRESS, serum sickness, hepatitis, hemolytic anemia, nephritis. Basically anything type II-IV on Gell-Coombs