CN1: Allergic Conditions Flashcards

Question

What are central to the development of type I hypersensitivity?

Answer 1

Mast cells and basophils

Answer 2

Mast cells

Answer 3

Basophils are **not** normally present in tissues

Answer 4

Near the blood vessels Nerves Subepithelial sites | where local type I rxns tend to occur

Answer 5

Mast cell cytoplasm

Answer 6

Acid proteoglycans ## Footnote stained granules often acquire a color that is different from that of the native dye, they're referred to as *metachromatic granules.*

Answer 7

Mast cells and basophils

Answer 8

C5a and C3a | anaphylatoxins ## Footnote both act by binding to their receptors on the mast cell membrane

Answer 9

the presence of **cell surface IgE Fc receptors** as well as **cytoplasmic granules** ## Footnote also: - both circulate in the blood in extremely small numbers - same to granulocytes, they can be recruited to inflammatory sites

Answer 10

- macrophage-derived cytokines (e.g., IL-8) - some drugs (codeine and morphine) - melittin (present in bee venom) - physical stimuli (e.g., heat, cold, sunlight)

Answer 11

Induction of CD4+ helper T cells of Th2 type | Th2 type are pivotal in the pathogenesis of the type I hypersensitivity ## Footnote type I rxns in humans = mediated by IgE

Answer 12

Presentation of the Ag (also called allergen) to precursors of TH2 by Ag-presenting dendritic cells.

Answer 13

IL-3, -4, -5, abd GM-CSF

Answer 14

further mast cell degranulation

Answer 15

edema, mucus secretion, and smooth muscle spasm ## Footnote many others, exemplefied by leukotrienes, PAF, TNF-a, and cytokines, set the stage for the late-phase response by recruiting additional leukocytes, basophils, neutrophils, and eosinophils.

Answer 16

Epithelial cells ## Footnote inflammatory cells also cause epithelial cell damage; epi cells aren't passive bystanders, they also produce SM

Answer 17

Chemokines eotaxin and RANTES ## Footnote impt in late-phse rxn = eo (favored by IL-5 & GM-CSF = from TH2 and mast cells)

Answer 18

Chemokines eotaxin and RANTES

Answer 19

Major basic protein and eosinophil cationic protein

Answer 20

Activated eosinophils and other leukocytes ## Footnote Thus, the recruited cells amplify and sustain the inflammatory response without additional exposure to the triggering antigen.

Answer 21

Late-phase reaction ## Footnote therefore, tx requires the use of broad-spectrum anti-inflammatory reagents s/a steroids

Answer 22

- complex dis resulting from an IgE-mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of Ag disposition. - events are regulated in large part by the induction of TH2-type helper T cells that promote synthesis of IgE and accumulation of inflammatory cells, particularly eosinophils - clinical features result from release of mast cell mediators and accumulation of an eosinophil-rich inflammatory exudate

Answer 23

Systemic anaphylaxis ## Footnote - the severity of the disorder varies with the level of sensitization - the shock dose of Ag, however, may be exceedingly small, as, for example, the tiny amounts used in ordinary skin testing for various forms of allergies. Within minutes after exposure, itching, hives and skin erythema appear, followed shortly thereafter by a striking contraction of respiratory bronchioles and the appearance of respiratory distress. - laryngeal edema results in hoarseness - vomiting, abdominal cramps, diarrhea, and laryngeal obstruction follow, and patient may go into shock and even die within an hour - effects of anaphylaxis must always be borne in mind when a therapeutic agent is administered - although patients at risk can generally be identified by a previous hx of some form of allergy, the absence of such a hx does not preclude the possibility of an anphylactic reaction.

Answer 24

Systemic anaphylaxis

Answer 25

Local anaphylaxis

Answer 26

Local anaphylactic rxns

Answer 27

50% of atopic individuals ## Footnote familial predisposition is NOT clear; but studies px w asthma reveal linkage to several loci, some map near the genes whose product regulate IgE response candidate genes have been mapped to 5q31, where genes for cytokines IL-3, -4, -5, -9, IL-13, and GM-CSF are located linkage has also been noted to 6p, close to the HLA complex

Answer 28

5q31 Also 6p (close to HLA complex)

Answer 29

higher serum IgE

Answer 30

TH2 pathways

Answer 31

Type II hypersensitivity ## Footnote The antigenic determinants may be instrinsic to the cell membrane, or they may take the form of an exogenous Ag, such as drug metabolite, absorbed on the cell surface. In either case, the hypersensitivity rxn results from the binding of Ab to normal or altered cell-surface Ag. Has 3 Ab-dependent mechanisms

Answer 32

Complement-Dependent Reactions

Answer 33

Antibody-Dependent Cell-Mediated Cytotoxicity

Answer 34

Antibody-Mediated Cellular Dysfunction

Answer 35

1) Direct lysis 2) Opsonization

Answer 36

Ab (IgM or G) reacts w Ag present on cell surface --> cause activation of complement system --> MAC (disrupts membrane integrity by drilling holes thru lipid bilayer)

Answer 37

The cells become susceptible to phagocytosis by fixation of Ab or C3b fragment to the cell surface (opsonization)

Answer 38

Type II hypersensitivity

Answer 39

1) transfusion rxns 2) erythroblastosis fetalis 3) AIHA 4) pemphigus vulgaris 5) certain drug rxns

Answer 40

Target cells coated w low conc of IgG Ab

Answer 41

Myasthenia gravis

Answer 42

Graves' dse

Answer 43

TYPE III HYPERSENSITIVITY (IMMUNE COMPLEX MEDIATED)

Answer 44

Type III hypersensitivity (immune complex mediated)

Answer 45

(1) exogenous Ag (s/a foreign CHON, bact or virus (2) under some circumstances, the individual can produce antibodies against self components – endogenous antigens. ## Footnote The latter can be trace components present in the blood, or more commonly, antigenic components in cells and tissues. Immune-complex mediated diseases can be generalized, if immune complexes are formed in the circulation and are deposited in many organs, or localized to particular organs, such as the kidney (glomerulonephritis), joints (arthritis), or the small blood vessels of the skin if the complexes are formed and deposited locally (the local Arthus reaction). These two patterns are considered separately.

Answer 46

Local Arthus rxn

Answer 47

Acute serum sickness

Answer 48

Acute serum sickness ## Footnote It is now seen infrequently and in different clinical settings. For example, serum sickness may occur after administration of horse antithymocyte globulin for treatment of aplastic anemia or antibiotic therapy for microbial diseases.

Answer 49

Anti thymocyte globulin

Answer 50

1. Formation of antigen-antibody complexes in the circulation and 2. Deposition of the immune complexes in various tissues, thus initiating 3. An inflammatory reaction in dispersed sites throughout the body ## Footnote The first phase is initiated by the introduction of antigen into the circulation and its interaction with immunocompetent cells, resulting in the formation of antibodies. Approximately 5 days after serum injection, antibodies directed against the serum components are produced, these react with the antigen still present in the circulation to form antigen-antibody complexes formed in the circulation are deposited in various tissues. The factors that determine whether immune complex formation will lead to tissue deposition and disease are not fully understood, but two possible influences are the size of the immune complexes and the functional status of the mononuclear phagocyte system: ○ Large complexes formed in great antibody excess are rapidly removed from the circulation by the mononuclear phagocyte system cells and are therefore relatively harmless. The most pathogenic complexes are of small or intermediate size (formed in slight antigen excess), circulate longer, and bind less avidly to phagocytic cells. ○ Because the mononuclear phagocyte system normally filters out the circulating immune complexes, its overload or intrinsic dysfunction increases the probability of persistence of immune complexes in circulation and tissue deposition. In addition, several other factors, such as charge of the immune complexes (anionic versus cationic), valency of the antigen, avidity of the antibody, affinity of the antigen to various tissue components, three-dimensional (lattice) structure of the complexes, and hemodynamic factors, influence their tissue deposition. ○ In addition to the renal glomeruli, the favored sites of immune complex deposition are joints, skin, heart, serosal surfaces, and small blood vessels. ● For complexes to leave the microcirculation and deposit within or outside the vessel wall, an increase in vascular permeability must occur. This is believed to occur when immune complexes bind to inflammatory cells through their Fc or C3b receptors and trigger release of vasoactive mediators as well as permeability-enhancing cytokines. ● Once complexes are deposited in the tissues, they initiate an acute inflammatory reaction (phase three). During this phase (approximately 10 days after antigen administration) ○ Activation of the complement cascade and ○ Activation of neutrophils and macrophages through their Fc receptors

Answer 51

Increase vascular permeability

Answer 52

Immune complex bind to inflammatory cells through their Fc or C3b receptors and trigger vasoactive mediator release and permeability enhancing cytokines

Answer 53

1. Release of C3b, the opsonin that promotes phagocytosis of particles and organisms 2. Production of chemotactic factors, which direct the migration of polymorphonuclear leukocytes and monocytes (C5 fragments, C5b67) 3. Release of anaphylatoxins (C3a and C5a), which increase vascular permeability and cause contraction of smooth muscle 4. Formation of membrane attack complex (C5-9), causing cell membrane damage or even cytolysis ## Footnote ● Neutrophils and macrophages can be activated by immune complexes even in the absence of complement. These cells have Fc receptors for IgG and therefore can bind to the Fc portion of the antigen-complexed IgG. ○ When several Fc receptor molecules are so occupied by aggregates of immune complexes, the inflammatory cells are activated. ● With either scenario, phagocytosis of antigen-antibody complexes by leukocytes drawn in by chemotactic factors results in the release or generation of a variety of additional proinflammatory substances, including prostaglandins, vasodilator peptides, and chemotactic substances, as well as several lysosomal enzymes including proteases capable of digesting basement membrane, collagen, elastin and cartilage. ○ Tissue damage is also mediated by free oxygen radicals produced by activated neutrophils. ○ Immune complexes have several other effects. They cause aggregation of platelets and activate the Hageman factor; both of these reactions augment the inflammatory process and initiate the formation of microthrombi. ○ The resultant pathologic lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomerulus, arthritis if it occurs in the joints, and so on. ● It is clear from the foregoing that complement-fixing antibodies (i.e., IgG and IgM) induce these lesions. Because IgA can activate complement by the alternative pathway, IgA-containing complexes may also induce tissue injury. ○ The important role of complement in the pathogenesis of the tissue injury is supported by the observation that experimental depletion of serum complement levels greatly reduces the severity of the lesions as does depletion of neutrophils. ○ During the active phase of the disease, consumption of complement decreases the serum levels.

Answer 54

● The morphologic consequences of immune complex injury are dominated by acute necrotizing vasculitis, with deposits of fibrinoid and intense neutrophilic exudation permeating the entire arterial wall. Affected glomeruli are hypercellular because of swelling and proliferation of endothelial and mesangial cells, accompanied by neutrophilic and monocytic infiltration. The complexes can be seen on immunofluorescence microscopy as granular lumpy deposits of immunoglobulin and complement and an electron microscopy as electron dense deposits along the glomerular basement membrane. ● If the disease results from single large exposure to antigen (e.g., acute poststreptococcal glomerulonephritis and acute serum sickness), all lesions tend to resolve, owing to catabolism of the immune complexes. A chronic form of serum sickness results from repeated or prolonged exposure to an antigen. ● Continuous antigenemia is necessary for the development of chronic immune complex disease because, as stated earlier, complexes in antigen excess are the ones most likely to be deposited in vascular beds. This occurs in several human diseases, such as systemic lupus erythematosus (SLE), which is associated with persistent exposure to autoantigens. Often, however, despite the fact that the morphologic changes and other findings suggest immune complex disease, the inciting antigens are unknown. Included in this category are rheumatoid arthritis, polyarteritis nodosa, membranous glomerulonephritis, and several other vasculitides.

Answer 55

● The Arthus reaction is defined as a localized area of tissue necrosis resulting from acute immune complex vasculitis usually elicited in the skin. ● The reaction can be produced experimentally by intracutaneous injection of antigen in an immune animal having circulating antibodies against the antigen. ● Because of the excess antibodies, as the antigen diffuses into the vascular wall, large immune complexes are formed, which precipitate locally and trigger the inflammatory reaction already discussed. ● In contrast to IgE-mediated type I reactions, which appear immediately, the Arthus lesion develops over a few hours and reaches a peak 4 to 10 hours after injection, when it can be seen as an area of visible edema with severe hemorrhage followed occasionally by ulceration. Immunofluorescent stains disclose complement, immunoglobulins, and fibrinogen precipitated within the vessel walls, usually the venules. ● On light microscopy, these produce a smudgy eosinophilic deposit that obscures the underlying cellular detail, an appearance termed fibrinoid necrosis of the vessels. Rupture of these vessels may produce local hemorrhages, but more often the vascular lumens undergo thrombosis, adding an element of local ischemic injury.

Answer 56

Cause aggregation of plts Activate Hageman factor - both augment inflammatory process and initiate formation of microthrombi

Answer 57

Vasculitis

Answer 58

the severity of lesions as does depletion of neutrophils

Answer 59

Consumption of complement decreases the serum lvls

Answer 60

Acute necrotizing fasciitis

Answer 61

Continuous antigenemia

Answer 62

Complexes in Ag excess

Answer 63

Arthus rxn

Answer 64

Immunofluorescent stains

Answer 65

Light microscopy

Answer 66

● The cell-mediated type of hypersensitivity is initiated by specifically sensitized T lymphocytes. It includes the classic delayed-type hypersensitivity reactions initiated by CD4+ T cells and direct cell cytotoxicity mediated by CD8+ T cells. ● It is the principal pattern of immunologic response not only to a variety of intracellular microbiologic agents, particularly Mycobacterium tuberculosis, but also to many viruses, fungi, protozoa, and parasites. ● So-called contact skin sensitivity to chemical agents and graft rejection are other instances of cell mediated reaction. Two forms of type IV hypersensitivity are described next:

Answer 67

● The classic example of delayed hypersensitivity is the tuberculin reaction, which is produced by the intracutaneous injection of tuberculin, a protein-lipopolysaccharide component of the tubercle bacillus. In a previously sensitized individual, reddening and induration of site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside. ○ Morphologically, delayed-type hypersensitivity is characterized by the accumulation of mononuclear cells around small veins and venules, producing a perivascular “cuffing”. ○ There is an associated increased microvascular permeability caused by mechanisms similar to those in other forms of inflammation. ○ Not unexpectedly, there is an escape of plasma proteins, giving rise to dermal edema and deposition of fibrin in the interstitium. ○ The latter appears to be the main cause of induration, which is characteristic of delayed hypersensitivity skin lesions. ● In fully developed lesions, the lymphocyte-cuffed venules show marked endothelial hypertrophy and, in some cases, hyperplasia. Immunoperoxides staining of the lesions reveals a preponderance of CD4 (helper) T lymphocytes. ● With certain persistent or non degradable antigens, such as tubercle bacilli, the initial perivascular lymphocytic infiltrate is replaced by macrophages over a period of 2 or 3 weeks. ○ The accumulated macrophages often undergo a morphologic transformation into epithelium-like cells and are then referred to as epithelioid cells. ○ A microscopic aggregation of epithelioid cells, usually surrounded by a collar of lymphocytes, is referred to as granuloma. This pattern of inflammation that is characteristic of type IV hypersensitivity is called granulomatous inflammation. ● The sequence of cellular events in delayed hypersensitivity can be exemplified by the tuberculin reaction, which begins with the first exposure of the individual to the tubercle bacilli. ○ Naive CD4+ T cells recognize peptides derived from tubercle bacilli in association with class II molecules on the surface of monocytes or epidermal dendritic (Langerhans) cells. ○ This initial encounter drives the differentiation of naive CD4+ T cells to Th1 cells. The induction of Th1 cells is of signal importance because the expression of delayed hypersensitivity depends in large part on the cytokines secreted by Th1 cells. ○ Why certain antigens preferentially induce the Th1 response is not entirely clear, but the cytokine milieu subsequently. ○ Some of the sensitized Th1 cells so formed enter the circulation and remain in the memory pool of T cells for long periods, sometimes years. ○ On intracutaneous injection of tuberculin in an individual previously exposed to tubercle bacilli, the memory Th1 cells interact with the antigen on the surface of antigen-presenting cells and are activated (i.e., they undergo blast transformation and proliferation). ○ These changes are accompanied by the secretion of the Th1 type cytokines, which are responsible for the expression of delayed-type hypersensitivity. Cytokines most relevant to this reaction and their actions are as follows: ■ IL-2, a cytokine produced by macrophages, is critical for the induction of the Th1 response and hence delayed hypersensitivity. On initial encounter with a microbe, the resting macrophages attempt to phagocytose and kill the organism. The resting macrophages are not particularly adept at these functions. Nevertheless, this interaction leads to the production of IL-12, which, in turn, produces other cytokines, listed below. IL-12 is also a potent inducer of IFN-γ secretion by T cells and NK cells. IFN-γ further augments the differentiation of Th1 cells. ■ IFN-γ has many effects and is an extremely important mediator of delayed-type hypersensitivity. It is a powerful activator of macrophages, causing further secretion of IL-12. Activated macrophages are altered in several ways. Their ability to phagocytose and kill microorganisms is markedly augmented; they express more class II molecules on the surface, thus facilitating further antigen presentation; their capacity to kill tumor cells is enhanced; and they secrete several polypeptide growth factors, such as platelet-derived growth factor and TGF-β, that stimulate fibroblast proliferation and augment collagen synthesis. Thus activated, macrophages serve to eliminate the offending antigen, and if the activation is sustained, fibrosis results. ■ IL-2 causes autocrine and paracrine proliferation of T cells, which accumulate at sites of delayed hypersensitivity; included in this infiltrate are some antigen-specific CD4+ Th1 cells and many more bystander T cells activated by IL-2. ■ TNF-α and lymphotoxin are two cytokines that exert important effects on endothelial cells: 1. Increased secretion of prostacyclin, which, in turn, favors increased blood flow by causing local vasodilation; 2. Increased expression of E-selectin, an adhesion molecule that promotes attachment of the passing lymphocytes and monocytes, and secretion of low-molecular weight chemotactic factors such as IL-8. ○ Together, all these changes in the endothelium facilitate the extravasation of lymphocytes and monocytes at the site of the delayed hypersensitivity reaction. ○ The process of which T cells and monocytes exit the vasculature is generally similar to that described for neutrophils. Involved is initial rolling on the endothelium, followed by up-regulation of integrin and firm adhesion, and, ultimately, transmigration through the vessel wall. ● This type of hypersensitivity is a mechanism of defense against a variety of intracellular pathogens, including mycobacteria, fungi, and certain parasites, and may also be involved in transplant rejection and tumor immunity. In addition to its beneficial, protective role, delayed-type hypersensitivity can also be a cause of disease. ○ Contact dermatitis is a common example of tissue injury resulting from delayed hypersensitivity. It is evoked by coming in contact with urushiol, the antigenic component of poison ivy or poison oak, and manifests in the form of a vesicular dermatitis. ○ The basic mechanism is similar to that described for tuberculin sensitivity. On reexposure to the plants, the sensitized CD4+ cells of the Th1 type first accumulate in the dermis, then migrate toward the antigen within the epidermis. ○ Here they release cytokines that damage keratinocytes, causing separation of these cells and formation of an intraepidermal vesicle. In this form of delayed hypersensitivity reactions, especially those that follow viral infections, cytokine-producing CD8+ T cells may be the dominant effector cells

Answer 68

● In this variant of type IV hypersensitivity, sensitized CD8+ T cells kill antigen bearing target cells. Such effector cells are called cytotoxic T lymphocytes (CTLs). ○ CTLs directed against cell surface histocompatibility antigens play an important role in graft rejection. ○ They also play a role in resistance to virus infections. In a virus-infected cell, viral peptides associate with the class I molecules within the cell, and the two are transported to the cell surface in the form of a complex. It is this complex that is recognized by the TCR of cytotoxic CD8+ T lymphocytes. ○ The lysis of infected cells before viral replication is completed leads, in due course, to the elimination of the infection. ○ It is believed that many tumor-associated antigens may also be similarly presented on the cell surface. CTLs therefore may also be involved in tumor immunity. ● Much has been learned about mechanisms by which CTLs kill their targets, and this knowledge may be of value in therapeutic modulation of T cell-mediated cytotoxicity in the settings of some autoimmune diseases. ○ Two principal mechanisms of T cell-mediated damage have been discovered: (1) Perforin-granzyme-dependent killing and (2) Fas-Fas ligand-dependent killing. ○ Perforins and granzymes are soluble mediators contained in the lysosome-like granules of CTLs. As its name indicates, perforin can perforate the plasma membranes of the target cells that are under attack by CD8+ lymphocytes. ○ At first, CD8+ T cells come in close contact with the target cells that are under attack by CD8+ lymphocytes. ○ This is followed by polymerization of the perforin molecules and their insertion into the target cell membranes, thus “drilling holes” into the membrane. These pores allow water to enter the cells, thus causing osmotic lysis. ● The lymphocyte granules also contain a series of proteases called granzymes, which are delivered into the target cells via the perforin-induced pores. ○ Once within the cell, granzymes activate apoptosis of the target cells by a different mechanism. ○ Activated CTLs express Fas-ligand, a molecule with homology to TNF-α, that can bind to Fas expressing target cells. This interaction leads to apoptosis.

Answer 69

CD8+ T cells

Answer 70

CD4+ T cells

Answer 71

Tuberculin rxn

Answer 72

Tuberculin - intracutaneous injection

Answer 73

8-12 hrs | Peak: 24-72 hrs then slowly subside

Answer 74

Escape of plasma proteins

Answer 75

Immunoperoxides staining of leison

Answer 76

Macrophages over a pd of 2 or 3 wks

Answer 77

Plt derived growth factor | TGF-B

Answer 78

(1) inc secretion of prostacyclin --> inc blood flow --> local vasodilation (2) inc E-selectin

Answer 79

E-selectin

Answer 80

(1) perforin-granzyme-dependent killing | (2) Fas-fas ligand-dependent killing

Answer 81

Step 1: DD Step 2: etiologic agent Step 3: detection of specific allergen ## Footnote ● For practical purposes, there are three types in making an allergy diagnosis. ○ Step 1: pertains to the differential diagnosis. All possible causes should be considered in an orderly manner. ○ Step 2: deals with how we arrive at an etiologic diagnosis, whether it is allergic or non allergic. ○ Step 3: is detection of the specific allergen/s involved. ● After confirming that the symptoms are truly allergic, a more specific diagnostic evaluation is in order to identify the antigen or antigens responsible for producing the symptoms. ● In addition, other variable factors should be assessed. ○ The degree of sensitivity to an antigen may vary in the same way that the degree of exposure to a clinically significant antigen varies. ○ Patients can be sensitive to multiple antigens and cumulative effects of exposure to several antigens may be important. ● Furthermore, the influence of non-immunologic factors on the symptoms has to be evaluated like the influence of infection, inhaled irritants, fatigue, emotional factors and others. It is important to note whether these significantly influence the allergic problem. ○ Independently or cumulatively with other non-immunology factors or with the allergic or immunologic factors. ○ Or whether they vary widely in degree of significance. Because of these variables, one should consider carefully-taken history as the most important aspect of the clinical evaluation in pediatric allergy.

Answer 82

Urticaria-angioedema Atopic dermatitis Anaphylaxis ## Footnote 1. Itching ● Urticaria – angioedema ● Atopic dermatitis ● Anaphylaxis 2. Skin rash/eruptions ● Urticaria – angioedema ● Atopic dermatitis ● Anaphylaxis ● Cow’s milk allergy 3. Sneezing ● Allergic rhinitis ● Anaphylaxis 4. Rhinorrhea (runny nose) ● Allergic rhinitis ● Cow’s milk allergy 5. Diarrhea ● Anaphylaxis ● Food allergy 6. Vomiting ● Food allergy 7. Bloody stools ● Cow’s milk allergy

Answer 83

Urticaria-angioedema Atopic dermatitis Anaphylaxis Cow's milk allergy

Answer 84

Allergic rhinitis | Anaphylaxis

Answer 85

Allergic rhinitis | Cow's milk allergy

Answer 86

Anaphylaxis | Food allergies

Answer 87

Cow's milk allergy

Answer 88

Food allergy

Answer 89

Non specific tests: 1. Smear of secretion for eosinophils 2. CBC and eosinophil count 3. Erythrocyte Sedimentation Rate (ESR) 4. Radiography 5. Stool examination 6. Urinalysis 7. Total IgE (PRIST) Specific Tests: Specific tests will identify the offending agent (specific IgE) causing the allergy symptoms. There may be no need to proceed to the second set of tests if the first set, in correlation with the careful history, suggests that the problem is not allergic 1. Skin test 2. Radio allergo-sorbent test (RAST) 3. Provocative or challenge test 4. Patch Test Routine Laboratory Tests 1. Blood count and ESR ● There are no abnormalities associated with the blood count and ESR in patients with allergic disease except for an eosinophilia of 3-7%. ● Higher eosinophil counts are seen in non- allergic asthma. ● Eosinophils in the respiratory tract secretions in patients with rhinorrhea or cough is a more useful diagnostic sign in allergy. ● A finding of greater than 5-10% eosinophils in nasal bronchial secretions is abnormal which is also true in the case of blood eosinophilia greater than 15% or 35% eosinophils/cmm. ● The presence of eosinophilia usually suggests that the patient’s symptoms will be sensitive to corticosteroid therapy, but it does not always suggest the presence of an allergy. ● The urine and stool of patients with unexplained urticaria will help rule out other non-allergic diseases. Ascariasis may explain pronounced blood eosinophilia. 2. X-ray ● Chest X-ray may be necessary to rule out concomitant asthma as well as its complications. X-ray films of the paranasal sinuses are indicated occasionally in patients suspected to have sinusitis. 3. In Vitro tests A. IgE measurement 1. PRIST: the paper radio-immunoabsorbent test is the most commonly used method in the measurement of total IgE. Asthma, allergic rhinitis and atopic dermatitis as seen in. Increased levels of IgE in typical forms of atopic dermatitis are of utmost importance in the differential diagnosis since they help support the diagnosis. Such findings likewise of IgE in typical forms of atopic dermatitis are of utmost importance in the differential diagnosis since they help support the diagnosis. Such findings likewise provide useful information regarding the likelihood of a child subsequently developing an atopic disease. 2. RAST: just like any antibody, the finding of an elevated level of IgE will have to be reinforced by the information as to the specific antigens present in the IgE. This can be achieved by the radio- allergosorbent test (RAST). The correlation between RAST and provocation tests range from 75% to 100%. The RAST also correlates closely with the prick test as well as with clinical history. It is quite an expensive test so that most allergies would prefer to do skin testing first and use RAST in special situations like patients with widespread eczema, very young infants or in instances wherein the result of the skin test does not correlate with clinical history. B. Histamine release test ● The histamine release test is a very sensitive test in allergy diagnosis and is reproducible. In this test, histamine is released and measured an hour after the antigen is added to the basophils in the blood of a sensitive individual. This test is employed more in research laboratories than in clinical practice. 4. In Vivo tests ● The most commonly utilized technique for the demonstration of sensitivity of a patient to a number of offending agents is the skin test. ○ A small amount of the antigen is introduced into the skin either by prick or intradermal technique. ○ A wheal-flare reaction is seen if the patient is sensitive to the injected antigen. Type I or immediate type of hypersensitivity reaction is the basis for the phenomenon. ● Following the encounter of the specific antigen with cell- bound IgE antibody, there is release of vasoactive amines from the mast cells which are responsible for the erythema, and wheal-flare reaction ● This response is immediate (within minutes) and its timing and size of weal are of diagnostic importance. As a general rule, the faster the reaction and the larger the size of the weal, the more clinically relevant is the test antigen. a. In vivo test: Skin test ● A late phase reaction at times is elicited and this occurs anywhere from 4 to 24 hours after the application of the test antigen. This latter response appears to be associated with the immediate IgE cutaneous responses and may also contribute to the late bronchial provocation response. ● False positive skin tests may occur with poorly prepared extracts containing non-specific irritants and after injection of excessive volume causing mechanical irritation. ● False negative reactions can be seen if the extract used is outdated or there is previous antihistaminic therapy, or in the very young and elderly. ● A positive skin test only demonstrates the presence of IgE antibody that is directed specifically against the test antigen. A positive test does not mean that the person has an allergic disease or that an allergic person has ever had a clinically significant reaction to the specific antigen. ● With inhalant antigens, correlation of positive skin test with history strongly suggests the presence of clinical sensitivity to the antigen. ● Conversely, a negative skin test and a negative history strongly suggest that the antigen is clinically insignificant. Particular attention must be used in the interpretation of the skin tests for food, since they are much less reliable. b. In vivo test: Provocation Challenge test ● Provocation challenge test is another method used to further document the sensitivity of a patient to an antigen. These procedures include conjunctival test in ophthalmic allergy, nasal and bronchial challenge in respiratory allergy as well as oral challenge in the case of ingestants. ● This test has been applied mostly in relation to asthma and allergic rhinitis. ● Bronchial provocation challenge tests can be performed by nebulisation of an aqueous antigen extract in the bronchial tree of the subject, and comparing its effects with that produced by an appropriate control solution. ● The effect on the pulmonary function is measured by the spirometer. The effect challenge is usually reflected in the fall of the forced expiratory volume (FEV) and expressed in the concentration of antigen necessary to produce 20% fall in FEV1.

Answer 90

``` Smear of secretion for eo CBC and eo ct ESR Radiography Stool exam Urinalysis Total IgE (PRIST) ```

Answer 91

Specific tests

Answer 92

1) skin test 2) RAST (radio allergo-sorbent test) 3) provocative or challenge test 4) patch test

Answer 93

1) bld ct 2) ESR 3) x-ray 4) in vitro tests (IgE and histamine tests) 5) in vivo (skin test and provocation challenge test)

Answer 94

● The overall goal in the treatment of allergic disorders is to prevent the recurrence of the allergic state after it has been diagnosed. This can be accomplished by the following objectives: 1. To adequately identify the causative allergens. 2. To remove the offending allergen/s from the patient’s environment. 3. To identify non-allergic triggers. 4. To avoid non-allergic triggers. 5. To use pharmacologic agents appropriately. 6. To institute allergy immunotherapy when total elimination of allergens is impossible. ## Footnote ● Allergic disease results from antigen antibody interaction that subsequently release mediators which are responsible for the clinical symptoms. ● Therefore, the management of allergic disorders is based on an effort to adequately identify the causative allergens. Identifications of such allergens are usually achieved with help of careful history taking and the judicious use of allergy skin testing. ● It must be remembered however, that elimination should not be based on the result of the skin test alone. It is only when the history and the skin test correlate that the allergens in question are said to be contributing the symptoms. ● The vital role of a physician is to remove the offending food, or an offending contactant like cosmetics. In other instances, the total elimination is impossible like the removal of house dust mites, mold or pollen. In these cases, allergy immune-therapy is often considered. ● Instructions should be rigid and detailed for the preparation of an allergy-free environment with special attention to the child’s bedroom. The non-allergic triggers have likewise to be identified and avoided. ● In many instances, the allergic state can be prevented by adequate avoidance of the environmental allergens and the use of appropriate pharmacologic agent

Answer 95

1. Avoidance of allergens or irritants 2. Pharmacologic therapy 3. Immunotherapy (hyposensitization or desensitization) 4. Prophylaxis ## Footnote ● Successful management of allergic disorders is based on avoidance of allergens or irritants, pharmacologic therapy, immunotherapy (hyposensitization or desensitization), and prophylaxis. ● Avoidance. When clinically relevant allergens are identified by history and judicious use of allergy skin tests, their elimination or avoidance is all that is needed in many cases of IgE-mediated disease. ○ If the history and skin testing indicate reactivity to house dust mite or molds, or if dog or cat allergen is contributing to the patient’s symptoms, these allergens should be eliminated from the home to the greatest extent possible. ○ The recommendation that a family pet be removed from a home is frequently difficult to implement. When the allergic disorder is a serious one, such as asthma, and when the child has a positive skin test result to the dog or cat allergen, parents can generally be persuaded to remove the animal. ○ When skin test results to dander are negative, the problem may be more difficult; most allergists believe that elimination of potentially sensitizing pets from the household of the allergic child is desirable prophylaxis. ● Allergy to house dust mites requires precautions to minimize exposure to mite allergens. ○ Avoidance in the bedroom is often sufficient because children spend more time there than in other rooms of the house. ○ Mattresses, box springs, and pillows should be encased in airtight, allergen-proof covers. Vacuuming the covered mattress at least weekly is necessary to remove mites. ○ Beddings should be washed at least weekly in hot water (>70C); cool water does not kill the mites. There should be no carpet or rug in the bedroom because either may be a rich source of mites. A small cotton throw rug may be acceptable if it is washed at least weekly in hot water. ● There should be no upholstered furniture and no stuffed toys in the bedroom. When removal or carpet froma bedroom is impossible, treatmentof the carpet with a solution of ltannic acid inactivates mite allergens. ○ Repeated treatments of the carpetintervals of 2-3 months are necessary because the solution does not kill the mites. Benzyl benzoate (Acarosan) kills mites; carpet treatment every few months is necessary to control mite population. Use tannic acid or benzyl benzoate is of less value than elimination of carpet. ● Household humidity should be kept at less than 50% to inhibit survival of mites. It is prudent to avoid use of vaporizers. ○ Dehumidifiers may be necessary in damp basements. Air conditioning helps to control humidity and also reduces exposure to atmospheric pollens and molds. ○ If elimination of a cat from home is impossible, other measures that can reduce allergen exposure include exclusion of the animal from the house, washing the cat more often than weekly, removal of carpets and upholstered furniture, and improvement of ventilation. ○ Cat allergen is ubiquitous in public places and homes without cats. ● Pharmacologic therapy is a major element in the management of diseases. ○ The drugs used have specific roles in the interruption of pathways leading to tissue damage as a consequence of antigen-antibody interaction. ○ Certain drugs, for example, modulate the antigen-induced release of mediators (histamine, leukotrienes) or block their actions; others affect the tension of smooth muscle and still others prevent migration to the site of an allergic reaction of inflammatory cells having the potential for producing tissue injury. ● Immunotherapy is appropriate for the treatment of allergic rhinitis or asthma mediated by IgE antibody-antigen interactions caused by unavoidable inhalant allergens. ● A predisposition to form IgE antibodies to substances of “high” allergenic potential is an important characteristic of the atopic state. ○ Therefore, prevention of exposure of infants and children at risk has a rational basis. It is appropriate to recommend breast-feeding for infants born into families with strong histories of hay fever, asthma or atopic dermatitis and to delay for at least 6 months the introduction of solid foods into the diet of such infants, especially foods of highly allergenic potentials such as eggs, cow milk, wheat, fish, citrus fruit, and peanut butter. ○ The nursing mother should avoid highly allergenic foods in her diet because there is evidence that the breast-fed infant can become sensitized to food antigens that are transmitted in breast milk. It is not definitively established whether postponing cow milk feedings in an atopic infant can prevent the development of cow milk allergy, of allergic diseases in general or of atopic dermatitis in particular, although there is some evidence of such effects ● Environmental exposure to high concentrations of house dust mite allergen is a risk factor for subsequent sensitization and asthma. ○ There are no prospective studies that indicate convincingly that avoidance of environmental exposure of atopic infants and children to other inhalant allergens such as dog and cat allergen lessens the likelihood of their sensitization, although such a result seems reasonable.

Answer 96

Erythema Multiforme minor

Answer 97

Erythema Multiforme ## Footnote ● Skin lesions may appear 3 to 14 days after insult (infection, drug, etc.) and new lesions can continue to appear for up to 10 days. ● Mucous membrane involvement, if present, is painful and debilitating. Fever, malaise, and weakness may also be present.

Answer 98

● Type: macules progressing to papules, vesicles and bullae ● Color: dull red rings alternating with cyanotic or violaceous rings ● Size: 1 to 2 cm ● Shape: target or iris lesions are typical ● Distribution: symmetric and bilateral, any parts of the body ● Sites of Predilection: palms, soles, dorsa of hands and feet, extensor surface of arms/legs, mucous membrane, oral, ocular and genital blistering and ulceration may be present. ● Other organs: pulmonary and renal involvement may also occur ## Footnote DIFFERENTIAL DIAGNOSIS ● Erythema Multiforme can be confused with viral exanthems, bullous diseases, urticaria, secondary syphilis, psoriasis or pityriasis rosea MICROSCOPIC CHARACTERISTICS ● Skin biopsy reveals dermal edema with a perivascular lymphocytic infiltrate and extravasated red blood cells. Necrotic keratinocytes lead to epidermal bullae formation

Answer 99

Erythema Multiforme minor

Answer 100

Erythema Multiforme major ## Footnote ● Rash appears and worsens until the precipitating cause is removed (i.e., discontinuation of drug). ● Rash is extensive with bullous lesions and >two mucous membranes are involved with systemic complication. ● Cheilitis stomatitis interferes with eating, vulvitis, and balanitis complicate micturition. ● Conjunctivitis and keratitis can lead to ocular impairment and lesions in the pharynx, larynx and trachea can occlude the airway. ● Fever and prostration are seen.

Answer 101

Conjunctivitis | Keratitis

Answer 102

Fever and prostration

Answer 103

Erythema Multiforme minor

Answer 104

Paper radio-immunosorbent test (PRIST)

Answer 105

Asthma Allergic rhinitis Atopic dermatitis

Answer 106

Radio-allergosorbent test (RAST)

Answer 107

Wheal-flare rxn

Answer 108

Type I or immediate type

Answer 109

Erythema Multiforme

Answer 110

Erythema Multiforme minor

Answer 111

Erythema Multiforme major

Answer 112

Erythema Multiforme minor

Answer 113

Erythema Multiforme minor

Answer 114

Erythema Multiforme major

Answer 115

Vaccination CT disorders Rarely malignancy

Answer 116

Cell-mediated cytotoxic rxn

Answer 117

Type: Macules progressing to papules, vesicles, and bullae Color: dull red rings alternating w cyanotic or violaceous rings Size: 1-2cm Shape: Target or iris lesions are typical Distribution: Symmetric and bilateral, any parts of the body Sites of predilection: palms, soles, dorsa of hands and feet, extensor surface of arms/legs Mucous membrane: oral, ocular, genital blistering and ulceration may be present Other organs: Pulmonary and renal involvement

Answer 118

* Viral exanthems * Bullous dses * Urticaria * Secondary syphilis * Psoriasis * Pityriasis rosea

Answer 119

Skin biopsy: dermal edema w a perivascular lymphocytic infiltrate and extravasated RBCs Necrotic keratinocytes

Answer 120

Necrotic keratinocytes

Answer 121

Solution of tannic acid

Answer 122

2-3 months

Answer 123

2-3 months

Answer 124

Benzyl benzoate (Acarosan)

Answer 125

Less than 50%

Answer 126

Pharmacologic therapy

Answer 127

Immunotherapy

Answer 128

Predisposition to form IgE Ab to substances of "high" allergenic potential

Answer 129

Envi exposure to high conc of house dust mite allergens

Answer 130

Faster rxn and larger wheal size

Answer 131

False positive skin test

Answer 132

False negative rxn

Answer 133

Positive skin test

Answer 134

Challenge test

Answer 135

Challenge test

Answer 136

Challenge test

Answer 137

Bronchial provocation challenge tests

Answer 138

Allergic dse

Answer 139

1. Avoidance of allergens or irritants 2. Pharmacologic therapy 3. Immunotherapy (hyposensitization or desensitization) 4. Prophylaxis

Answer 140

Allergic Rhinitis

Answer 141

Allergic Rhinitis

Answer 142

1. sneezing 2. rhinorrhea – watery and profuse 3. nasal obstruction 4. itching of the nose, palate, pharynx and ears 5. itching, redness and tearing of the eyes 6. “rabbit nose” – wrinkling of nose to relieve itching and obstruction 7. “allergic salute” – rubbing of itchy nose

Answer 143

1. Eosinophilic non-allergic rhinitis 2. Primary nasal mastocytosis 3. Neutrophilic (infectious rhinitis) 4. Vasomotor rhinitis

Answer 144

1. Avoidance of allergens and irritants 2. Immunotherapy if unable to avoid allergens 3. Drug therapy – Antihistamines, decongestants, sympathomimetic – Nose drops sprays – short-term only to avoid rebound vasodilation and severe nasal obstruction – Cromolyn nasal solution (prophylaxis) – Topical corticosteroids (spray) – most effective – Leukotriene antagonists

Answer 145

Urticaria angioedema (Hives)

Answer 146

Urticaria angioedema (Hives)

Answer 147

1. well-circumscribed sometimes coalescent, localized or generalized, erythematous, raised skin lesions 2. may be intensely pruritic or itch little 3. angioedema – edema of skin and submucosa or other tissues – upper respiratory and GIT 4. no laboratory tests establish the diagnosis

Answer 148

1. Self-limited in most instances requiring little treatment other than antihistamines 2. Epinephrine – for active severe forms 3. Hydroxyzine – for cholinergic and chronic urticaria

Answer 149

Atopic dermatitis

Answer 150

Atopic dermatitis

Answer 151

1. erythematous, weepy patches in the cheeks then face, neck, wrists, hands, abdomen, and extensor aspect of extremities, later flexural areas. 2. marked pruritus 3. “mask of atopic dermatitis” – whitish hue and blanching of surrounding tissue 4. hyperpigmentation, scaling and lichenification 5. family history of asthma, hay fever of atopic dermatitis 6. increased IgE; eosinophilia 7. white dermatographism 8. atopic pleat or Dennie’s line or Morgan’s fold – accentuated lines/grooves below the margin of lower eyelids 9. sparsity of hair of the lateral portion of the eyebrows secondary to chronic rubbing

Answer 152

1. seborrheic dermatitis 2. scabies 3. primary irritant dermatitis 4. allergic contact dermatitis 5. infectious eczematoid dermatitis 6. Wiskott-Aldrich syndrome

Answer 153

1. Avoidance of ingestant, injectant, contactant and atmospheric factors that can trigger itching 2. Extremes of temperature and humidity should be avoided 3. Garments – smooth-textured cotton. Wool should be avoided 4. Avoid soaps and detergents 5. Use bath oils, creams, or lotions 6. Local therapy wet dressings with Burrow’s solution 7. topical corticosteroid lotions or creams 8. antihistamines 9. antibiotics for secondary bacterial infection 10. topical steroid ointment after the acute phase subsides

Answer 154

Food allergy

Answer 155

1. History 2. Allergy-like symptoms 3. Detection of high levels of histamine in the implicated food 4. Skin test Clinical Manifestations: 1. GIT, vomiting, abdominal pain, diarrhea, bloody stools, protein-losing enteropathy, fat malabsorption 2. respiratory rhinorrhea, wheezing (rarely) 3. skin eczema, urticaria 4. CNS seizures, lethargy, headache, anxiety

Answer 156

1. Avoidance – elimination of offending food from the diet 2. pharmacologic therapy – antihistamines, cromoglycate, self-administered epinephrine to prevent serious systemic reactions 3. immunotherapy hyposensitization has not been successful so far but further studies are needed

Answer 157

Cow’s milk allergy

Answer 158

Cow’s milk allergy

Answer 159

1. critical testing of foods by elimination and provocation method in a blind manner to eliminate emotional bias 2. skin testing with properly prepared food antigens 3. for cow’s milk allergy and anaphylactic food allergy, the history alone establishes the diagnosis During the first year of life: 1. vomiting 2. watery, blood-streaked mucoid diarrhea 3. gastroesophageal reflux 4. enteropathy with loss of both protein and blood (in infants fed with whole pasteurized milk) 5. older infants – occult fecal blood loss, recurrent pulmonary infiltrates on x-ray, and multiple precipitating antibodies to cow milk proteins 6. enteropathies with varying combinations of malabsorption, steatorrhea, hypoalbuminemia, and fecal blood loss

Answer 160

1. food allergy – nuts, eggs, seafoods, milk 2. immune-mediated (e.g. celiac disease) 3. food additives – dyes, MSG, metabisulfite 4. food poisoning – botulinism, Clostridium perfringens, S. aureus 5. infections – Salmonella, E.coli, rotavirus, etc. 6. contaminants – heavy metals, antibiotics 7. pharmacologic agents – caffeine, tyramine, alcohol, histamine 8. GI disorders – GE reflux, pyloric stenosis, T-E fistula, etc. 9. enzyme deficiencies – galactosemia, PKU 10. malabsorption syndromes – lactose deficiency, cystic fibrosis 11. psychologic – school phobia 12. functional – irritable bowel syndrome, chronic non-spec. Diarrhea of infancy

Answer 161

1. treatment is directed at the clinical manifestations 2. offending food should be removed from the diet. The prescribed diet should be nutritionally adequate and will not impair the growth 3. most infants with IgE-mediated allergy to cow’s milk tolerate soy well but others are sensitive to it and may require the substitution of a protein hydrolysate 4. infants not able to tolerate hydrolysates are given amino acid-derived infant formulas

Answer 162

Drug allergy

Answer 163

Drug allergy

Answer 164

1. accurate and detailed history needed for diagnosis 2. symptoms resemble hypersensitivity reactions such as anaphylaxis and serum sickness 3. diagnostic tests – skin test, RAST

Answer 165

Pseudo allergic drug reaction

Answer 166

1. Withdrawal of offending agent 2. Pharmacologic ▪ Antihistamines – diphenhydramine 1-2mg/kg/dose 3-4 times a day ▪ Sympathomimetics – epinephrine 1:1000 – 0.01ml/kg subcutaneously ▪ Corticosteroids Prednisone 1-2mg/kg/24 hrs in divided doses not to exceed 60mg orally

Answer 167

Allergic contact dermatitis

Answer 168

Allergic contact dermatitis

Answer 169

– extensive history – careful physical examination – exclusion of diseases characterized by eczematous lesions

Answer 170

1. feet lesions are symmetrically sparing the interdigital spaces 2. blisters in lines and streaks 3. earlobe, neck, wrist dermatitis 4. axillary dermatitis 5. dermatitis on other parts of the body where there is contact with the allergen

Answer 171

1. Eosinophilic non-allergic rhinitis 2. Primary nasal mastocytosis 3. Neutrophilic (infectious rhinitis) 4. Vasomotor rhinitis

Answer 172

1. Antihistamines e.g., diphenhydramine and hydroxyzine 2. Warm water compresses to remove medications applied at home 3. Avoid substances that might further irritate or sensitize the damaged skin 4. To relieve inflammation in the acute phase: Cool H2O compresses kept moist and in place for at least 45 minutes 3x daily 5. Corticosteroid creams 6. For disseminated skin lesions: short-course systemic corticosteroid, 2mg/kg per day in divided doses 7. For infectious, suspected, or present-topical erythromycin

Answer 173

Forearm 4 finger-width below AC

Answer 174

< or = 0.5mL

Answer 175

1/2 to 5/8

Answer 176

Tuberculin syringe

Answer 177

Erythema Multiforme minor ● Rash self-resolves in 5 to 15 days. ● Symptomatic relief can be obtained with the following: a. Bath with colloidal oatmeal b. Emollients c. Topical steroids are effective if used in appropriate strength d. Antihistamines may be somewhat helpful in controlling itchiness e. Severe cases may require systemic steroids f. Control of herpes outbreaks in recurrent cases of EM minor with prophylactic acyclovir is indicated Erythema Multiforme major ● Identification and elimination of the precipitating agent is critical. ● Supportive care includes: a. Wound care, including baths with gentle cleaners b. Topical steroids in appropriate strength (15% hydrocortisone, 25% hydrocortisone) c. Widespread denudation of the skin requires hospitalizations and thermoregulation and food administration (especially in cases with extensive oral involvement). Systemic steroids are of questionable efficacy. Constant culture and local debridement should be done to prevent infection and risk of sepsis until skin fully heals