OVER-REACTIONS OF THE IMMUNE SYSTEM.pptx

Importance of Immune Reactions in Allergy

1. OVER-REACTIONS OF THE
IMMUNE SYSTEM

Hypersensitivity Reactions and
Allergic Diseases

2. OVER-REACTIONS OF THE
IMMUNE SYSTEM

e Hypersensitivity reactions
— Adaptive immune response to harmless molecules
— Sensitization of immune system required
— Mediated by antibody and effector T cells
— Allergic diseases
° Disease following immune response to allergens
° Allergens

— Harmless molecules which cause type |
hypersensitivity reactions

3. Common sources of allergens

Inhaled materials

Plant pollens

Dander of domesticated animals

Mold spores

Feces of very small animals
e.g., house dust mites

Injected materials

Insect venoms
Vaccines

Drugs

Therapeutic proteins

Figure 10-1 part 1 of 2 The Immune sn 2/e (© Garland Science 2005)

4. PICKLES

\ DIDN'T REALIZE
YOU HAD THIS MANY
‚EMILY, NO
WONDER YOUVE +
DEVELOPED AN
ALLERGY, y

\ TRY TO KEEP
THE CAT DANDER
UNDER CONTROL.
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1 MAY HAVE

6. Common sources of allergens

Ingested materials

Food
Orally administered drugs

Contacted materials

Plant leaves

Industrial products made from
plants

Synthetic chemicals in industrial
products

Metals ‘poison ivy nickel coin

Figure 10-1 part 2 of 2 The Immune me 2/e (© Garland Science 2005)

7. CLASSIFICATION OF HYPERSENSITIVITY
REACTIONS (GELL AND COOMBS)

Based on immune reactant, antigen and effector
mechanism

Type I

Mediated by IgE against soluble antigens with mast
cells, basophils and eosinophils

Type I
Mediated by IgG and IgM against cell surface / matrix
antigens with complement and phagocytes

8. CLASSIFICATION OF HYPERSENSITIVITY
REACTIONS (GELL AND COOMBS)

Based on immune reactant, antigens and effector
mechanism

Type III
Mediated by IgG against soluble antigens with
complement and phagocytes

Type IV
Mediated by CD4 and CDS cells against soluble and
cell surface antigens with macrophages and CD 8 T
cells

9. Cell- or matrix-
an ||| associated ||| are
antigen

Complement, ;
Effector Mast-cell Poke cells ” Antibody

mechanism activation hagocytes, alters
Nice) signaling

Example of Allergic rhinitis, | Some drug [Chronic urticaria
hypersensitivity | asthma, systemic} allergies (antibody to
reaction hylaxis (eg penicillin) FaRla)

Fiaure 10-2 part 1 of 2 The Immune System. 2/e (© Garland Science 2005)

10. Type Ill Type IV
Immune

Soluble Soluble Soluble Cell-associated
antigen antigen antigen antigen

Effector Complement ||| Macrophage Eosinophil u
mechanism Phagocytes activation activation Cytotoxielty

Contact
Serum sickness, dermatitis,
Arthus reaction tuberculin

reaction
Figure 10-2 part 2 of 2 The Immune System, 2/e (© Garland Science 2005)

Example of
hypersensitivity
reaction

Chronic asthma,
chronic allergic
rhinitis

Contact
dermatitis

11. TYPE I HYPERSENSITIVITY
REACTIONS

* Normal physiological role of IgE
* Defense against parasites
Pathophysiological role of IgE
* Allergy
* Greater knowledge
* Type I reactions follow sensitization to allergens
* Sensitization
* First exposure to allergen elicits an IgE response
* Genetic predisposition (Atopy)

12. TYPE I HYPERSENSITIVITY
REACTIONS
THE IgE RECEPTOR

IgE binds (Fc fragment) with high affinity to
FceRI receptor

FeeRI receptor
* Mast cells, basophils, activated eosinophils

* Binding of IgE results in sensitization of cells

IgE functions as allergen receptor

13. ANTIGEN RECEPTORS ON MAST CELLS,
BASOPHILS AND ACTIVATED
EOSINOPHILS

* Different from receptors on T and B cells
* Effector function becomes operational immediately
following antigen binding
* Cell proliferation and differentiation not required

* Receptors are not restricted to a single antigen
specificity

* Features provide a strong and quick response to
antigens for a sensitized person

14. MAST CELLS (MASTOCYTES)

* Originate in bone marrow from CD34 progenitor
* Basophils may have same progenitor

* Development of immature cells at tissue sites
* Types
* Mucosal
* Tryptase production
* Development T cell dependent
* Connective tissue
* Chymotryptase production

* Express high levels of IgE receptor

16. MECHANISM OF TYPE I
HYPERSENSITIVITY REACTIONS

FcéRI receptor expressed constitutively
* Mast cells and Basophils
* Activated eosinophils

Allergen binding results in cross-linking of
receptors

Cross-linked receptors signal degranulation of
cytoplasmic granules

Degranulation results in release and synthesis
* Inflammatory mediators, toxins, enzymes

18. Tryptase, chymase, 1 aes Hh pr
cathepsin G, carboxypeptidase Remodeling of connective tissue matrix
5 se Toxic to parasites
Toxic mediator Histamine, heparin Increase vascular permeability
Cause smooth muscle contraction

Promotes inflammation, stimulates cytokine
TNF-« (some stored
production by many cell types, activates
preformed in granules) rene
IL-4, IL-13 ‘Stimulate and amplify Ty2-cell response
IL-3, IL-5, GM-CSF Promote eosinophil production and activation
Chemotactic for monocytes, macrophages,
mi | pe and people

Cause smooth muscle contraction
Leukotrienes C,, D, and Ey Increase vascular permeability
Cause mucus secretion
Lipid mediator
Chemotactic for leukocytes
Platelet-activating factor Amplifies production of lipid mediators
Activates neutrophils, eosinophils, and platelets

Figure 10-5 The Immune System, 2/e (© Garland Science 2005)

19. HISTAMINE (BIOGENIC AMINE)

Exerts a variety of physiological effects following binding
to specific receptors (H1, H2, H3)

Allergic reactions
* Histamine binds to HI receptors

Physiological effects
* Constriction of bronchial / intestinal smooth muscle
* Increased permeability of blood vessels
* Increased secretion of mucus by goblet cells
* Leukocyte chemotaxis

20. LEUKOTRIENES

Classified as lipid mediators of inflammation
* Derived from arachidonic acid via lipoxygenase pathway
* Produced by mast cells, monocytes and granulocytes

Leukotrienes (LTA4 — LTE4)
* pay: { Eu
Sustain inflammatory response in allergic disease
* Autocrine and paracrine mechanisms
* C, D and E are cysteinyl leukotrienes
* Increased levels induce anaphylaxis

Physiological effects similar to histamine
* More potent / longer lasting than histamine
* Vasodilation, bronchoconstriction, neutrophil chemotaxis

21. PROSTAGLANDINS

Classified as lipid mediators with a variety of physiologic
effects

* Normal

* Inflammation

Derived from arachidonic acid
* Cyclooxygenase pathway

Act locally and rapidly metabolized

Produced by all nucleated cells except lymphocytes

22. Arachidonic acid 5-lipoxygenase
Cyclooxygenase pathway

pathway

Prostaglandin PGD,
Active A Inactive
'ostaglandin synthase) 2 prostaglandin synthase;
+

Aspirin
(acetyl salicylate)

Salicylate

Figure 10-7 The Immune System, 2/e (© Garland Science 2005)

23. CYCLOOXYGENASE PATHWAY

* Prostaglandins produced by two different enzymes
* Cyclooxygenase-1 (Cox-1)
* Cyclooxygenase-2 (Cox-2)

* Cox-1 involved in normal physiological functions
* Stomach mucus production
3 2 :
Kidney water excretion
* Platelet function

* Cox-2 involved in inflammatory response

24. Membrane phospholipids

|

Arachidonic acid

endotoxins
cytokines (TNF)
RS mitogens
COX-1 COX-2
prostaglandins prostaglandins

thromboxanes prostacyclins

(influence gastric,
renal and platelet
function)

Normal font - main pathways
Bold - enzymes
Boxed italics (in red) - drug effects

25. NONSTEROIDAL ANTI-
INFLAMMATORY DRUGS (NSAIDS)

* Reduce pain, inflammation and fever by inhibition of
cyclooxygenase pathway
* Non-Selective (Cox-1 and Cox-2 inhibitors)
* Acetylsalicyclic acid (Aspirin)
* Ibuprofen (Motrin, Advil)
* Indomethacin (Indocin)
* Naproxen (Naprosyn, Aleve)
* Selective (Cox-2 inhibitors)
* Celecoxib (Celebrex)
* Rofecoxib (Vioxx)
* Valdecoxib (Bextra)

26. How COX-2 Inhibitors Work

PAIN RELIEF: 4 COX-2 is an enzyme that is activated at sites of injury. 2 COX-2 inhibitors are drugs designed to block
It manufactures hormone-like substances called prostaglandins, which the activity of the COX-2 enzyme and relieve
trigger paintul inflammation pain

CO \
TN

cox-2
Inhibitors

4 Researchers believe that when COX-2 is
blocked, prostacyclin may also be suppressed,
HEART RISK: 3 Prostacyclin, a prostaglandin produced by COX-2 in blood allowing platelets to stick together and blood
vessel walls, opens blood vessels and prevents platelets from clumping vessels to constrict, which can lead to heart
Platelets attacks and strokes

» \ y
d )
» = - m Constricted

Prostacyclin Clumped Vessel Walls
Dilated Vessel Walls Platelets

28. EOSINOPHILS

* Granulocytic leukocytes (1 — 6% in blood)
* Level variation (down in am, up in pm)

* Granules
* Orange to reddish-orange in color
* Uniform in size and evenly distributed

* Toxins, enzymes, cytokines and inflammatory
mediators

* Mature cells reside in
* Blood and lower GI tract

29. Toxic to targets by catalyzing halogenation
ni E ein | a ed IE

Eosinophil collagenase
Major basic protein

Remodeling of connective tissue matrix
Toxic to parasites and mammalian cells
Triggers histamine release from mast cells

Toxic protein

[ssrepietone protein

Toxic to
Neuroto)

rasites

Neurotoxin

Cytokine

IL-3, IL-5, GM-CSF

Amplify eosinophil production by bone marrow
Cause eosinophil activation

Chemokine

CXCL8

Promotes influx of leukocytes

Leukotrienes Cy, D, and Ez

Platelet-activating factor

Lipid mediator

Cause smooth muscle contraction
Increase vascular permeability
Cause mucus secretion

Chemotactic to leukocytes
Amplifies production of lipid mediators
Activates neutrophils, eosinophils, and platelets

Figure 10-9 The Immune System, 2/e (0 Garland Science 2005)

30. EOSINOPHILS

* Eosinophil response
* Parasites (Helminths)
* Main effector cell in allergy and asthma
* Induced by drugs, diseases and radiation
* Eosinophilia potentially toxic to host

* Control mechanism for host toxicity
Panes ear :
Limiting bone marrow production

* Regulated expression of Fc-epsilon-RI
* IgE receptor not expressed in resting state

32. CASE STUDY - 58 YEAR OLD
FEMALE

* Laboratory
— CBC with differential
= 12,000 leukocytes with 10% eosinophils
— Sputum for eosinophils
= Unable to produce

* Radiology
— CXR and CT

* Endoscopy
— Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL)

36. CASE STUDY — EOSINOPHILIC
PNEUMONIA

° Pulmonary eosinophilia or eosinophilic lung disease

° Classification
— Primary (idiopathic)
— Secondary
= Parasitic or fungal infection
= Immunological or systemic disease
» Asthma, HIV, malignancy
= Drugs
» Antibiotics, NSAIDS, L-tryptophan

° Mechanism of disease 1s unknown

37. CASE STUDY - 23 YEAR OLD MALE

* Presents to family physician with 2 year history of
— Dysphagia
— Episodes of food impaction
= Breads and meats

° Past and present medical history
— Seasonal allergic rhinitis
— Non-smoker

38. CASE STUDY - 23 YEAR OLD MALE

° Laboratory

— CBC with differential
= 12,000 leukocytes with 11% eosinophils

° Endoscopy with esophageal biopsy
— Endoscopy showed “ringed esophagus”

° Surgical Pathology Report
— > 20 eosinophils/HPF (proximal and distal)
— Areas of basal cell hyperplasia suggests reflux
— No viral CPE, dysplasia or malignancy

41. — Proton pump inhibitors (Nexium) ?

42. BASOPHILS

Granulocytic leukocytes (0 — 1% in blood)

* Granules

* Violet-blue in color
* Variable in size and unevenly distributed
* Contents similar to mast cells

Mature cells reside in blood

* Basophils similar to mast cells

* Constitutive expression of IgE receptor
* Significant source of IL-4

* Both interact with eosinophils

44. IgE MEDIATED ALLERGIC
REACTIONS

IgE production is favored following
* Chronic exposure to proteins or chemicals bound to
proteins
* Low molecular weight, soluble, glycosylated
proteins
Allergens promote CD4 TH2 response when interleukin-4
is present
Interleukin-4 promotes IgE isotype switch in cognate
interaction with B cells
IgE response amplified following release of IL-4 by
activated mast cells and basophils

45. SENSITIZATION TO AN INHALED
ALLERGEN

Majority of allergens are components of dried particles
derived from plant and animals

Majority of allergens in US are proteases
* Cysteine protease in feces from house dust mite
* Dermatophagoides pteronyssimus
* Papain from papaya fruit

* Significance of enzymatic activity of allergens is unknown

46. |

MHC class II

Figure 10-14 The Immune System, 2/e (© Garland Science 2005)

47. Figure 10-15 The Immune System, 2/e (© Garland Science 2005)

48. GENETIC PREDISPOSITION TO TYPE I
HYPERSENSITIVITY

* Atopy

* Genetic propensity to produce IgE antibodies in
response to allergens
* Atopic response characterized by elevated levels
* IgE and eosinophils
* Multiple genes are involved
* Chromosome 2
* Regulation of T cell activation
* Chromsome 5
* Gene cluster for IL-3, IL-4 and IL-13
* Chromosome 11
* Beta chain of FceRI receptor

49. TWO STAGES OF TYPE I
HYPERSENSITIVITY REACTIONS

* Immediate reaction (Stage 1)
* Appears within 30 minutes
* Subsides within 30 minutes

* Late phase reaction (Stage 2)

* Appears 6 to 8 hours after immediate reaction
has subsided

* Subsides within 24 hours
*
Examples
* Wheal and flare (skin)
* Breathing capacity (lungs)
* Forced expiratory volume in 1 second (FEV1)

50. Late-phase

Figure 10-16 The Immune System, 2/e (© Garland Science 2005)

51. Asthmatic response to inhaled allergen

Immediate Late-phase

34] Antigen
FEV, challenge
(liters) à

30 12 Time
minutes

Figure 10-17 The Immune System, 2/e (© Garland Science 2005)

52. SPECTRUM OF TYPE I ALLERGIC
DISEASES

Allergic rhinitis (hay fever)

Allergic conjunctivitis

Allergic rhinoconjunctivitis (ARC)
Allergic asthma

Eczema

* Atopic dermatitis

* Allergic contact eczema (dermatitis)
Allergic urticaria (hives) and angioedema
Food allergy
Anaphylaxis (Anaphylactic shock)

53. ALLERGIC RHINITIS (HAY FEVER)

Inflammation of mucous membranes of

* Nose

ho Eyes, eustachian tubes, ears, sinuses, pharynx
* Symptoms

* Sneezing, itching, rhinorrhea, nasal congestion, fatigue
* Tearing, postnasal drip, earache, sinus pressure
Genetic predisposition for offspring

* 1 (30%) or 2 (50%) parents with AR

* Classification

* Seasonal (tree, grass, ragweed pollens)
* Perennial (dust mites, cockroaches, animal dander)

54. ALLERGIC RHINITIS (HAY FEVER)

* Prevalence in US of 20%
ee y
Diagnosis
* History and physical
* Laboratory studies
* Differential diagnoses
> ee
Sinusitis
* Viral rhinosinusitis
* Vasomotor or non-allergic rhinitis
* Hormonal rhinitis
* Rhinitis medicamentosa
* NARES

55. *

*

*

*

LABORATORY DIAGNOSIS OF
ALLERGIC RHINITIS (HAY FEVER)

Nasal cytology

* Wright stained smear of nasal secretions
CBC with differential

Serum IgE (total)

Allergy testing
* Skin test

* Prick or puncture techniques
* Blood test

* ImmunoCAP system

57. Inhaled antigen enters mucosa and
activates mucosal mast cells locally

Mast-cell activation causes blood-
vessel permeability and
activation of epithelium

Eosinophils are recruited from blood
and enter nasal passages with mucus

nasal passage nasal epithelium

a 5

Figure 10-21 The Immune System, 2/e (© Garland Science 2005)

61. IMMUNOCAP SPECIFIC IgE BLOOD
TEST

* Quantitative measurement of specific IgE levels to
numerous allergens by FEIA
* Fluoresence Enzyme Immunoassay (FEIA)

* Consists of reaction chamber with solid phase of cellulose
sponge matrix

* Specific allergens covalently linked to solid phase
* Specific IgE levels expressed as kU/L
+ ;

Interpretation

* Seven concentration classes (0-6) from < 0.35 to > 100.00
* Negative, equivocal, positive (2), strongly positive (3)

63. PREVENTION AND TREATMENT OF
ALLERGIC RHINITIS

* :
Prevention
* Avoidance of offending allergens

* Treatment / Prevention
* Antihistamines
* Decongestants
* Leukotriene receptor antagonists
* Anti-inflammatory agents
* Mast cell stabilizing agents

* Immunotherapy (Hyposensitization / Desensitization)

64. ANTIHISTAMINES (ORAL) FOR
ALLERGIC RHINITIS

* Mechanism of action

* Prevent binding of histamine to HI receptors

* Blood vessels, GI tract, respiratory tract

* Antihistamines (1% generation)
* Sedating

* Chlorpheniramine (Chlortrimeton)
* Diphenhydramine (Bendryl)

65. ANTIHISTAMINES (ORAL) FOR
ALLERGIC RHINITIS

* Antihistamines (2"¢ generation)

* Low-sedating or non-sedating
* Cetirizine (Zyrtec)
* Levocetirizine (Xyzal)
* Fexofenadine (Allegra)
* Loratadine (Claritin)
* Loratadine (Alavert)
* Desloratadine (Clarinex)

66. — | to 2 sprays per nostril BIL

+ Adverse events
— Bitter taste, headache, somnolence:

° Precaution
— Avoid concurrent use with alcohol and other CNS depressants

67. n Antihistamine Weekly TRx Share
USC Classes 14100 & 14310 Dec

— Generic Clarin
Genero Allegra
Allegra D

— Chrinex

Aston

—ynD

—Alega

— sind

Se 3 ee US u Ei fe = © à

Source: MS Healh, AG Edwards estimates

12

68. DECONGESTANTS FOR ALLERGIC
RHINITIS

* Mechanism of action

* Decrease hyperemia by vasoconstriction
* Activate alpha-adrenergic receptors of respiratory tract

* Decongestants (oral)
* Pseudoephedrine (Sudafed)
* No longer OTC but BTC
* Phenylephrine (Sudafed PE)
* Phenylpropanolamine
* AR of hemorrhagic stroke
* Decongestants (intranasal)
* Oxymetazoline

69. SUDAFED

12 HOUR

Pseudoephedrine Hydrochloride

Extended-Release Tablets
LONG-ACTING NASAL DECONGESTANT

+ Nasal & Sinus Congestion SS
due to Colds & Allergies

+ Sinus Pressure 20 COATED CAPLETS*

+ Maximum Strength 120 mg EACH

*CAPSULE-SHAPED TABLETS,

70. Take 1 to the pharmacy register.
Lleve 1 a la caja de la farmacia.

Allergy & Congestion

EXTENDED
seep ASEH, 10 Es overs @

71. Original Prescription Strength

Non-Drowsy”

Claritin-D 24

Pseuaoephearme Sulfate 240 mg/Nasal Decongestant
Loratadine 10 mg/Antihistamine

A ae EXTENDED
HD Facts Panel, IS Release ras.ers “>

72. Pe EE LL tee. À

74. ANTIHISTAMINE / DECONGESTANT
COMBINATIONS

FOR ALLERGIC RHINITIS

* . .
First generation
* Chlorpheniramine + pseudoephedrine
(Chlortrimeton-D)

* Diphenhydramine + pseudoephedrine
(Bendryl-D)

* Second generation
* Cetirizine + pseudoephedrine (Zyrtec-D)
* Fexofenadine + pseudoephedrine (Allegra-D)
* Loratadine + pseudoephedrine (Claritin-D)

75. ANTI-LEUKOTRIENE AGENTS FOR
ALLERGIC RHINITIS

* Leukotriene receptor antagonists
* Montelukast (Singulair)

* Mechanism of action
* Binds to CysLT1 receptor with no agonist activity

* Precautions
* Avoid aspirin (NSAIDS) if aspirin sensitive
* Neuropsychiatric events
* Changes in behavior and mood

76. NASAL STEROIDS FOR ALLERGIC
RHINITIS AND ARC

* Considered most effective for prevention and treatment
Mechanism of action is unknown

* Wide range of effects on many inflammatory cells and
mediators

* Control all major symptoms

* Corticosteroids

* Fluticasone propionate (Flonase)

* Fluticasone furoate (Veramyst)

* Mometasone furoate (Nasonex)

* Triamcinolone acetonide (Nasacort)

* Beclomethasone dipropionate (Beconase)

77. Nasal Steroid TRx Share

USC Class 28420
ste Generic Flonase
45% +
Newer
40%
35% |
— Nasacon/Aqua
30%
= —R'inoowtaqu |
20%
15% — Forase
10%
5% ——Veramyst

1200s
aveoos 4
612008 4
ries |
91172006
srvze%e 4
7/1/2006 |
11112008
111/2007
anrzoor
rive0or |

371/2004
5/1/2004
71112004
9/1/2004

ve

Source: MS Heal, AG Edwards estimates

78. MAST CELL STABILIZING AGENTS
FOR ALLERGIC RHINITIS

° Cromolyn sodium
— Cromolyn (Nasalcrom) by nasal spray

° Mechanism of action
— Calcium ion channel blocker
= Intracellular Ca++ essential for degranulation

° Not as effective as corticosteroids

° Frequent dosing (1 spray q6h)

79. IMMUNOTHERAPY (ALLERGY SHOTS)
FOR ALLERGIC RHINITIS

Immunotherapy (allergy shots) indications
* Allergic rhinitis, allergic asthma and insect stings

* Allergy shot phases

Build-up (1-2 visits a week for 3-6 months)
* Maintenance (1 visit every 2-4 weeks for 3-5 years)

Mechanism
* Generation of allergen-specific regulatory T cells
* Secretion of IL-10 and TGF-beta
* Suppression of IgE and stimulation of IgG4 and IgA by B cells

80. ASTHMA

* Disease of the lower respiratory tract
* Types
* Allergic (extrinsic) asthma
* Symptoms triggered by inhalation of allergens
* Non-Allergic (intrinsic) asthma
* Symptoms triggered by factors not related to allergy
* Anxiety, stress, exercise, viruses, smoke and other
irritants

* Symptoms for two types are similar

81. ALLERGIC AND NON-ALLERGIC
ASTHMA

* Symptoms
* Shortness of breath (SOB), wheezing, chest
tightness, cough, fatigue
* Pathophysiology

* Characterized by inflammation, constriction and
mucus in tracheobronchial tree

* Prevalence in US
* 1 in 15 (20 m)

82. KNOXVILLE IS #1 nn
ASTHMA CAPITAL AGAIN ==

11
AsthmaCAPITALS
2008

83. Why asthma makes it hard to breathe

Air enters the respiratory system
from the n mouth and
ronchial tubes.

the muscles around the
tubes are relaxed
ue th

matic person, the
ne bronchial tubes

Inflamed bronchial tube
of an asthmatic Normal bronchial tube

can Academy of Allergy. Asthma and Immunalogy

84. Inflammatory mediators contract
smooth muscle, increase mucus
secretion from airway epithelium,
and increase blood vessel permeability
blood |
vessel /

muscle

Figure 10-22 The Immune System, 2/e (© Garland Science 2005)

Chronic response mediated by
cytokines and eosinophil products

“eosinóphil granul
¿proteins / à
à \(T2 ))

85. MANAGEMENT AND TREATMENT OF
ALLERGIC ASTHMA

* Bronchodilators (beta-antagonists)
* Albuterol (Proventil)

* Short acting
* Salmeterol (Serevent)

* Long acting

* Mast cell stabilizing agents
* Cromolyn (Intal) for inhalation

* Corticosteroids (oral, IV, inhaled)

* Prednisone (PO), Methylprednisolone (IV), inhaled
fluticasone (Flovent)

86. MANAGEMENT AND TREATMENT OF
ALLERGIC ASTHMA

* Leukotriene receptor antagonists
* Montelukast (Singulair)
* Zafirlukast (Accolate)

* Leukotriene synthesis inhibitors
* Zileuton (Zyflo)

* Anti-IgE monoclonal antibody
* Omalizumab (Xolair)

87. OMALIZUMAB (XOLAIR) IN ALLERGIC
ASTHMA

Indication

* Persons >12 years with moderate to severe disease not
controlled with ICS

* Positive for perennial acroallergen
IgG1 kappa monoclonal antibody to IgE
* Mechanism of action
* Reduces binding of IgE to FcéRI receptors
* Reduces number of receptors on basophils
à = :
Administration

* Subcutaneous every 2 to 4 weeks
* Bioavailability of 62%

88. SINGLE-USE VIAL

NDC 50242-040-62
LIST NO. 13013

olair
Omalizumab

FOR SUBCUTANEOUS USE

KEEP REFRIGERATED. DO NOT FREEZE

Genentech th NOVARTIS ix

93. ALLERGIC REACTIONS IN SKIN

* Urticaria (Hives)
* Red and itchy swelling of superficial skin
* Allergic and non-allergic etiology
* Acute and chronic (idiopathic) onset
* Chronic idiopathic urticaria
* 35% have autoimmune etiology
* Angioedema
* Swelling of skin with pain and burning
* Mouth, lips, tongue, hands
* Lower dermis and subcutaneous
* Allergic and non-allergic etiology

94. ALLERGIC REACTIONS IN SKIN

* Reactions occur following mast cell
activation
* Direct inoculation into skin
* During systemic anaphylaxis
* Following ingestion of food or drug carried
to skin by bloodstream

97. ALLERGIC REACTION TO FOOD

* Food allergy

* A reaction involving the immune system

* IgE
* Prevalence of 2% of adults and 6% of children
* Symptoms

* Tingling in mouth

* Swelling of lips, tongue, throat and face

* Abdominal pain, N/V/D

* Urticaria, eczema

* Dizziness, syncope

* Wheezing, SOB

98. ALLERGIC REACTION TO FOOD

* Top eight foods

* Milk, eggs, peanut, tree nuts (almonds,
pecans, walnuts), soybean, wheat, fish and shellfish

* Shellfish allergy
* Usually develops in young adults and is life-long
* Types of shellfish

* Crustaceans (shrimp, crab, lobster)
* Mollusks (clams, oysters, scallops)

99. ALLERGIC REACTION TO FOOD

* Fish allergy
* One of most common and most dangerous
* Tendency to be life-long
* Canned fish (tuna, salmon) less antigenic than fresh

* Peanut allergy
* One of most common and most dangerous
* Tendency to be life-long
* 35% show allergy to tree nuts

100. ALLERGIC REACTION TO FOOD

* Egg allergy
* One of most common in children
* Tendency to outgrow
* White contains allergenic proteins

* Milk (cow) allergy
* The most common in infants and young children
* Majority outgrow
* Not to be confused with lactose intolerance

101. ALLERGIC REACTION TO FOOD

* Oral allergy syndrome
* Fruits and vegetables trigger a mild allergic reaction
due to protein cross-reactivity
* Allergy to ragweed pollen
* Reaction to melons, bananas, tomatoes
* Allergy to grass pollens
* Reaction to melons, kiwis, tomatoes
* Allergy to birch pollen

* Reaction to apples, peaches, plums, cherries, nectarines,
carrots, celery

102. FOOD INTOLERANCE AND
MALADSORPTION

A reaction to foods (containing lactose and
fructose) not involving the immune system
+ E
Same signs and symptoms as food allergy
* Lactose intolerance
* Results from lactase deficiency
*

Fructose
* Intolerance
* Results from Adolase B deficiency
* Maladsorption

* Results from defective intestinal transport mechanism

103. ALLERGIC REACTION TO FOOD

* Food Allergy Initiative (www.faiusa.org)

* National 501 (c) non-profit organization founded in
1998 by concerned parents and grandparents

* Played major in passage of

* Food Allergen Labeling and Consumer Protection Act
(FALCPA) of 2004

* FALCPA (August, 2004)
* Under FDA
* January 1, 2006 start date
* August of 2008 to include gluten

104. ALLERGIC REACTION TO FOOD

* Gluten
* Proteins in wheat, barley, rye and sometimes oats
* Mixture of prolamins and glutelins
* Prolamins trigger reaction in small intestine
* Celiac disease
* Celiac disease
* Autoimmune disease
* Inflammation of mucosa leads to atrophy of villi

* Maladsorption

105. Supplement Facts

Amount Per Serving

Calories

Total Fat E 49
Salurated Fal

Cholesterol

Mangar
Chromium

Molyederum Ti

Protein Blend (Whey protein concentrate and rice
protein), Carbohydrate, Multi-Vitamin/Mineral Blend
{potassium chloride, dicalcium phosphate, magnesium
oxide, ascorbic acid, ferric orthophosphate, ribollavin
thiamin mononitrate. chromium picolinate, vitamin D3.
folic acid, biotin, potassium lodide, sodium malyndete,
vitamin K, sodium salenate, cyanocobalamin), stevia
natural chocolate flavors, carrageenan and lecithin.

106. Supplement Facts

Serving Size 2scoops te gi 4 scoops

Servings Per Container "

Amount Per Serving
Calories 500

Daily Value”

Cholesterol 55mg 18% 110m9
Carbohydrate 8% 28g 10%

30 ma 50%
20014 50%

Protein Blend (Whey protein concentrate from milk
and rice protein), Carbohydrate, Multi-Vitamin/Mineral
Blend (potassium chloride, dicalcium phosphate,
magnesium oxide, ascorbic acid, ferric orthophosphate,
iboflavin, thamin mononitrate, chromium picolinate.
vitamin DS from fish, falic acid, biotin. potassium
iodide, sodium molybdate, vitamin K, sodium selenate,
cyanocobalamin), stevia, natura’ chocolate flavors
from kola nut), carrageenan and lecithin (from soy)

Allergen Warning: Produced in a facility that also
processes egg, wheat, and shellfish products.

107. ANAPHYLAXIS

Acute, systemic (multi-system) reaction
Caused by allergens which reach bloodstream
* Venomous insect stings
* TV and IM drugs
* PO drugs (rapid absorption and high bioavailability)
* Foods

* Anaphylactoid reactions

*

Non-IgE mediated
* Clinical manifestations are same
* Cause is NSAIDS, radiographic dyes or idiopathic

108. Antigen in bloodstream enters
tissues and activates connective
tissue mast cells throughout the body

IgE-coated mast cells

blood capillary

SZ

Mast-cell degranulation and release
of inflammatory mediators

IT
2 25 4
Heart and vascular Respiratory Gastrointestinal
system tract tract
Increased capillary Contraction of smooth muscle| | Contraction of smooth muscle!
permeability and entry of and constriction of throat Stomach cramps
fluid into tissues and airways Vomiting
Swelling of tissues including Difficulty in swallowing Fluid outflow into gut
tongue Difficulty in breathing Diarrhea
Loss of blood pressure Wheezing
Reduced oxygen to tissues
Irregular heartbeat
Anaphylactic shock
Loss of consciousness

Figure 10-19 The Immune System, 2/e (© Garland Science 2005)

109. SIGNS AND SYMPTOMS OF
ANAPHYLAXIS

* Appear within minutes to hours of exposure

* Order of appearance
* Skin and soft tissue
* Flushing, pruritis, urticaria and angioedema
* Cardiovascular
* Syncope, tachycardia, irregular or no pulse
* Nervous
* Apprehension, convulsions
* Gastrointestinal
* Vomiting, diarrhea, abdominal cramps
* Respiratory
* Wheezing, dyspnea

110. TREATMENT OF SYSTEMIC
ANAPHYLAXIS

* E o :
Epinephrine is drug of choice
* Catecholamine drug (stress hormone) acting on

* Alpha receptors of vascular endothelium
* Beta receptors of bronchial smooth muscles
Administered by IM injection into anterolateral thigh
* Do not inject into buttock
* Do not inject IV
* Cerebral hemorrhage

* Epinephrine Auto-Injector (EpiPen)

* Adult (0.3 mg) and pediatric (0.15)

111. GA

Noc 2268-0302 0
DIN 00578657

112. —
o
o

ao
o

Epinephrine (nmol F') ==

Mir
-20

1
D
=
=
=
=
©
de
=
D
Y
ro
ee
a
Ss
m
©
=
©
=
E
©
=

20 40

0
AN Time (minutes)

Figure 10-20 The Immune System, 2/e (© Garland Science 2005)

113. ALLERGY TESTING

*

Methods of testing
* Skin and blood

* Skin testing
* Prick, puncture or scratch technique
* Skin reaction (wheal and flair) within 15 minutes
* Blood testing
* Measure serum IgE level
* Measure serum IgE level for allergen(s)
* CBC with differential

114. TYPE I HYPERSENSITIVITY
REACTIONS

*

Antibody mediated (IgG and IgM) cell destruction
* Mechanisms of cell destruction
* Activation of complement
* ADCC
* Opsonization
* Clinical settings
* Blood transfusion reactions
* Hemolytic disease of the newborn
* Drug-induced hemolytic anemia

115. TRANSFUSION REACTIONS

Transfusion of blood is a type of transplantation
ABO blood group antigens
* Glycoproteins on surface of erythrocytes
Blood types based on ABO and Rh antigens
* A,B, AB, O
* Rh + or—
Natural antibodies associated with ABO antigens
* Isohemagglutinins
Mechanisms

*

IgM mediated response to ABO antigens
IgG mediated response to Rh antigen

*

116. O antigen A antigen B antigen

117. Potential donor

Recipient

STA
Anti-A and anti-B
antibodies

EX

Anti-B antibodies

N °
Anti-A antibodies

AB

No antibodies
against A orB

Figure 12.30 The Immune System, ed. (© Garland Science 2009)

118. Red blood cells from individuals of type

Express the carbohydrate structures

IR-GlcNAc-Gal-GalNAc
Serum from R-GleNAc-Gal | R~GIcNAc-Gal-GalNAc| R-GicNAc-Gal-Gal Fuc
a : : +
individuals Fuc Fuc Fuc R-GleNAc-Gal- Gal
of type Fuc

ASAS
ne agglutination agglutination agglutination

Anti-A and anti-B||| agglutination
antibodies

A
nN Ec Es agglutination agglutination
| ee agglutination ||| agglutination 99 99
Anti-B antibodies

a
no inati no gs
agglutination ||| 299lutination [ll aoaiutination ||| agglutination
|Anti-A antibodies

AB
no no no no

No antibodies agglutination ||| agglutination ||| agglutination ||| agglutination
toAorB

Figure A-8 Immunobiology, 7ed. (© Garland Science 2008)

119. Copyright © 2006 Pearson Education, Inc., publishing as Benjamin Cummings.

120. DRUG-INDUCED HEMOLYTIC ANEMIA

* Drugs (soluble, small molecules) covalently linked to cell

surface proteins of human cells

* Drugs and cells

‘a

* Penicillin to erythrocytes
* Sulfamethoxazole to platelets

Results in altered antigen and IgG response with cell lysis
* Hemolytic anemia
* Thrombocytopenia

121. Penicillin

reactive bond

y

Penicillin binds to bacterial
transpeptidase and inactivates it

Penicillin modifies proteins on
human red blood cells to
create foreign epitopes

Serine

transpeptidase

Figure 10-26 The Immune System, 2/e (© Garland Science 2005)

122. Figure 10-27 The Immune System, 2/e (© Garland Science 2005)

123. Figure 10-28 The Immune System, 2/e (© Garland Science 2005)

124. TYPE III HYPERSENSITIVITY
REACTIONS

Mediated by immune complexes
* Formed by IgG and soluble antigens
IC cleared by phagocytes following complement fixation
Complement fixation influenced by size of IC
* Small
* CF is inefficient
* Circulate in blood and deposited in tissues
* Large
* CF is efficient
* Removed from blood with no tissue deposition
Size of IC influenced by concentration of antigen and
antibody

125. © Antigens combine with
antibodies to form
antigen-antibody complexes

Antigen

Antibody

Antigen-antibody complex

© rragocytes remove most
ofthe complenes, but
Some loage ln e walls
of blood vessels

© Mere the complexes
activate complement

Inactive complement

Active complement

© Antigen antibody complexes
and Betlvated Complerent
attract and activate
eutrophis which release
inflammatory chemicals

Neutrophil
Inflammatory chemicals
© inflammatory chemicals

damage underlying
blood vessel wall

126. Early in the response
there is little antibody
and an excess of antigen

Small immune complexes are
formed that do not fix comp-
lement and are not cleared
from the circulation

At intermediate stages in
the response, there are
comparable amounts of

antigen and antibody

Immune complexes are
formed that can fix
complement and are
cleared from the circulation

Figure 10-29 The Immune System, 2/e (© Garland Science 2005)

Late in the response
there are large amounts
of antibody and
little antigen

Immune complexes of inter-
mediate size are formed that
can fix complement and are
cleared from the circulation

127. TYPE III HYPERSENSITIVITY
REACTIONS

* Pathophysiology related to portal of entry of

antigen
1. Subcutaneous injection (Arthus reaction)
* Localized erythema and induration
2. IV administration (Serum sickness)
* Occurs 7 to 10 days following
* Horse serum, mouse monoclonal antibodies
* Characterized by fever, chills, skin rash...

3. Inhalation (Hypersensitivity pneumonitis)

* — Continued exposure to antigen with IC formation and
deposition on alveolar membranes

128. Resulting
disease

Intravenous
(high dose)

Subcutaneous

Inhaled

Site of immune-
complex
deposition

129. TYPE IV HYPERSENSITIVITY
REACTIONS

Delayed-type hypersensitivity reactions (DTH)
* Occur 1-3 days following antigen contact
* Large amount of antigen required

Mechanism of action
* Presentation of antigen to memory T cells
* CD4 THI, CD4 TH2 and CD8
Effector T cells secrete cytokines
* Macrophage activation, inflammation, tissue destruction

*

Examples
* Tuberculin skin test

* Contact with poison ivy

130. Type IV hypersensitivity reactions are mediated by antigen-specific effector T cells

Contact
hypersensitivity

Gluten-sensitive enteropathy
(celiac disease)

Syndrome Antigen Consequence
. Local skin swelling:
Proteins:
Delayed-type Insect venom Pyne:
hypersensitivity Mycobacterial proteins Cellular infiltrate
(tuberculin, lepromin) Dermatitis

Haptens:
Pentadecacatechol
(poison ivy)
DNFB

Small metal ions:

Local epidermal reaction:
Erythema
Cellular infiltrate
Vesicles

Nickel Intraepidermal abscesses
Chromate
Villous atrophy in
Gliadin small bowel

Malabsorption

Figure 12.35 The Immune System, 3ed. (© Garland Science 2009)

131. TUBERCULIN SKIN TEST (TST)

* Synonym
* PPD (purified protein derivative) skin test
* Identify infection with Mycobacterium tuberculosis
* Test procedure and interpretation
* Injection of TB protein intradermally
* Read reaction at 48 to 72 hours for induration (mm)
* Interpret induration based on risk factors
* 5 mm (high risk)
* 10 mm (moderate risk)
* 15 mm (low risk)

132. NDC 49281-752-2

Tuberculin Purified Protein
Derivative (Mantoux)

TUBERSOL®

133. + Inject intradermally 0.1 ml of 5
TU PPD tuberculin

+ Produce wheal 6 mm to 10 mm
in diameter

+ Do not recap, bend, or break
needles, or remove needles from syringes

» Follow universal precautions for infection control

135. + Read reaction 48-72 hours after| |
injection

+ Measure only induration

+ Record reaction in millimeters |

137. QuantiFERON-TB GOLD TEST
(Interferon-gamma release assay)

*

Blood test for
* Tuberculosis

* Latent tuberculosis infection (LTBI)

* Test procedure

* Whole blood mixed with M. tuberculosis antigens (peptides)
* ESAT-6
* CEP-10
* TB7.7 (p4)
* Incubation for 16 to 24 hours
* Measure quantity of interferon-gamma (IFN-gamma)
* Interpretation

*

IFN-gamma indicates CMI (memory T cells)

139. CONTACT WITH POISON IVY

* A contact dermatitis
* Involves both CD4 TH1 and CD8 T cells to

* Pentadecacatechol (urushiol oil)
* Langerhans’ cells process and present modified proteins
* Extracellular

* CD4 THI cells
* Intracellular

* CDS cells
* Transfer of pentadecacatechol from initial site of contact
* Delayed nature of reaction

142. Figure 10-36 The Immune System, 2/e (© Garland Science 2005)