Part 15. Allergic Disorders

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PART XV. Allergic Disorder                          

Chap 133. Allergy and Immunologic Basis of Atopic Disease

# Allergy

    ; specific, acquired change in host reactivity *mediated by an immunologic mechanism & causing an toward physiologic response

# *not all antigen are good allergens

# Common Characteristics Of Allergens

    ; protein in part

    ; acidic with molecular weight of 10000-70000 daltons

# Atopy

    ; hereditary factor

           - expressed as susceptibility to hay fever, asthma, & eczematoid dermatitis in the families of affected individuals

    ; ass. with HLA types

    ; ass. with chromosome 11q13

# Immunologic difference in atopy vs non-atopy

    ; *predisposition to selective synthesis of IgE Ab.to common environmental Ag.

    ; defective control of mediator release or generation

    ; impaired mediator inactivation processes

# Type of Immunologic reaction to the reactants

    ; interaction of humoral Ab. with Ag.

           - 3 forms

                   / two occurs on surface of cell an third in extracellular fluid

    ; interaction of Ag. with lymphocytes (=cell-mediated or delayed type hypersensitivity)

Type I Hypersensitivity, Mediated By Ige

(=immediate type or anaphylactic hypersensitivity)

; occurs on cell surface

; *circulating basophils and tissue mast cell

    --> sensitized through the binding of IgE Ab. to their surface receptors

    --> allergen interaction with cell-bound IgE antibody molecules

    --> immune tissue injury.

# Ultimate Outcome Contributing Factors

     ; broad spectrum of secondary events involving types of lymphoid cells, inflammatory cells, mediator-producing cells

    ; soluble products derived not only from all of these cells but from other tissues(platelets, endothelial cells) at site of reactions

# Reaginic IgE, IgE Reagins, Homocytotrophic Antibodies

    ; molecules with activities against specific allergen

    ; cf) nonspecific IgE

        - found in the serum & tissues of all normal individual

           - *defend against tissue-invasive parasites

    ; ass. with HLA-linked immune response(IR) genes

           - ragweed antigen Ra3 and HLA-A2

           - ragweed antigen Ra5 and HLA-B7

           - rye grass antigen I and HLA-B8

Formation of IgE reagins

Fig. 133-1 먼저 이해한 본문 숙독

# IL-1

    ; activation of presentation antigen to CD4 (helper T cell) cells

# *CD4 cells TH2 분화하여 IL-3, IL-4, IL-5,GM-CSF 합성분비한다.

# IL-4

    ; *isotype switching of B-cell 중요한 역활

           - IgG & IgM --> IgE

           - IgE 합성에 *IL-5(non-isotype B cell growh factor) & IL-6(non-isotype B cell differentiation factor) 필요하다.

# IL-5 & GM-CSF

    ; induce eosinophil differentiation

# IL-3 & IL-4

    ; mast cell growth factor

# Gamma Interferon

    ; *inhibit IL-4-dependent IgE synthesis

    ; *inhibit IL-4 induced expression of low-affinity IgE receptors(CD23) on B cell

Binding Of Ige Reagins To Mast Cells Or Basophils

; revisibly or fixed binding to surface receptors of mast cell or basophils

# receptors(FER)

    ; involve C4 & C3 domains of Fc portion of Ig molecule

    ; nonatopy - 20-50% occupied by IgE

    ; atopy - 100% occupied

# “sensitized”되었다고 말한다.

Events After Allergen-IgE Reagins Bindings

# Biochemical Reation

    ; activation of methyltransferase, phospholipid methylation, Ca++  influx, activation of phospholipid diacylglycerol cycle

    --> fusion of mast cell granules with plama membrane

    --> release of active substances(chemical mediators)

# Tissue reation by mediator-binding tissue receptor

    ; reversible

    ; mast cell, basophils not lysed

    ; *no participation of complement system

    ; early phase - 6~8hr

    ; late phase - 12~48hr

# Interaction of Cytokines with endothelial cell

    ; activated by IL-1

           --> upregulation of endothelial adhesion molecules(eg, E-selectin, ICAM-1, VCAM-1)

    ; activated by IL-4

           --> upregulation of VCAM-1.

    ; *lecitin-binding regions of selectins interacts with ligands on leukocytes

           --> rolling over endothelial cells

           --> interacts with *integrins, ICAM-1, VCAM-1

           --> arrest leukocytes

           --> facilitate movement out of vasculatures

# *Ligand For VCAM-1

    ; *very late activation antigen-4

# Histamine 일으키는 생체 반응 3가지

    ; increased capillary permeability

    ; increased capillary dilatation

    ; axon reflex stimulation

    --> familiar wheal & flare reaction

# Examples

    ; ragweed hay fever, anaphylactic reaction to insect venom, food-induced urticaria, allergic conjunctivitis or rhinitis

Type II Hypersensitivity (Cytotoxic) Interaction

; occur on cell surface

; *IgG or IgM reacts with allergens

; *activates complement system

# Examples

    ; transfusion of incompatible RBC

   - recipient's isohemagglutinin (Ab. directed against determinants  on the surface of RBC)  react with the incompatible cells

        --> complement system activation

        --> sequential action of complement proteins

           --> Iysis cell

    ; drug-induced immune hemolytic anemia

Type III  Immunopathologic Mechanism

; *occurs in extracellular space

; Ag-Ab. complex

    --> lodge in the filtering organs of body(kidney,lung)

    --> infiltrate the wall of small blood vessels

    --> *activation of complement cascade

    --> release of biologically active substance

  --> chemotaxis for PMN leukocytes

    --> *phagocytosis of complex

  --> release of basic protein & proteolytic enzymes from damage tissue

# Different Ab 관여

    ; leakiness of capillaries

           --> toxic complex 축적을 용이하게 한다.

# Examples

    ; *serum sickness, immune complex pericarditis or arthritis, glomerulonephritis

Type IV Cell-Mediated Or Delayed-Type Hypersensitivity

; innteraction of Ag.with specifically sensitized T Iymphocyte

    --> macrophage cytotoxic cell 중요한 역할을 하는 것으로만 알려져 있다.

# Examples

    ; *contact allergy, tuberculin reactivity, GVHD, tissue, transplantation reaction, infiltrative hypersensitivity lung ds

1331.1 Chemical Mediators Of Alleric Reactions & Mechanisms Of Realse

# Mast cell & basophils involved condition

    ; *IgE mediated reaction, chronic inflammatory disorders, rheumatoid arthritis, parasitic infection

# Activator Of Mast Cell

    ; cross-linking of receptor-bound IgE Ab. by multivalent specific Ag.

    ; purified Ab to IgE receptor

    ; *complement system (C3a, C5a)

  ; kinins

  ; *neutrophil-derived lysosomal basic protein

  ; lymphokines

# Biochemical Reaction Resulting Fusion Of Granule To Plasma Membrane

    ; change in membrane phospholipid metabolism

           - methylation and activation of phospholipases

           - generation of phospholipid by-products

    --> leading to extrusion of mast cell granules

# Biochemical Reaction during Mediator Release

    ; activation of serine esterase

  ; utilization of intracellular energy store

  ; calcium influx or remobilization of intracellular calcium

  ; change in the mast cell cytoskeleton

# Preformed Mediators

    ; histamine, eosinophil chemotactic factor , HMV-NCF, heparin, arylsulfatase B, trypsin, chymotrypsin, inflammatory factors

# Newly performed mediators

   ; Table 133-1

# Early phase 관여하는 Mediators

    ; histamine, ECF, other chemotactic factors

# Early & Late Phase 관여하는 Mediators

    ; heparin, arylsulfatase B, enzyme such as trypsin, chymotrypsin, inflammatory factors

# cAMP

    ; increase in intracellular conc.

           --> inhibition of release of mediators from mast cell

    ; prostaglandin E & beta-adrenergic agonist

           --> increase in cAMP

Factors Not Mast Cell-derived That Participate in Immediate-Type Hypersensitivity Diseases

Eosinophil- Derived Molecule

    ; eosinophil major basic protein (MBP)

    ; eosinophil peroxidase (EPO)

    ; eosinophil-derived neurotoxin (EDN)

    ; eosinophil cationic protein (ECP)

# Eosinophil Major Basic Protein (MBP)

    ; destruction of airway epithelium 야기하여  bronchial  hyperresponsiveness발생& basophil에서 histamine release자극

-> wheal & flare rx야기

eg) asthma, atopic dermatitis, chronic urticaria

Kinins  

- amplifier & effector property

 :chemotaxis, increased vascular permeability, & smooth m.  contraction

  bradykinin - the most important product of kinin system

              potent contractile effect on smooth m., increased  vascular permeability&

              dilates peripheral arteioles

              (특히 cold urticaria 증가)

              stimulate pain receptor

kinin generation & amplification

: activation of Hageman factor (factor X11) - initial step

--activated by tissue injury from IgG aggregates & immune complex

- converts prekallikrein to kallikrein

- kallikrein digest high molecular wt. kininogen to liberate

  vasoactive peptide bradykinin

Platelet-Activating Factor (PAF)

synthesized by vascular endothelial cell, monocytes, macrophage, neultrophil. eosinophil & platelet

poten  inducer of increased vascular permeability

bronchial hyperresponsiveness in normal subject

late phase reaction 야기

Type I Hypersensitivity Reaction

# Early Phase Reaction

    ; 10-30 min

  ; d/t release of performed & newly synthetized mast cell mediators

  ; vasodilation, edema from increased vascular permeability, smooth m. constriction (bronchoconstriction), mucus production

    ; treated with antihistamine & mast cell memb. stabilizer

# Late-Phase Reaction

    ; 4-8 hr

    ; recruitment of inflammatory cell

           - eosinophil, neutrophil, lyrnphocyte located in the perivascular space

    ; erythema, edema, induration, hyperirritability to rechallenge with allergen

    ; contribute to hyperresponsiveness in allergic children with asthma, rhinitis & atopic dermatitis

    ; poorly respond to antihistamine or bronchodilator but may respond to coriticosteroids

Serotonin ( 5-hydrotytryptamine)

: vasoactive amine

 smooth m. contraction & increased vascular permeability

 90% of body stores; G-I tract

 human mast cell내에는 거의 없음.

 diarrhea in carcinoid syndrome

 induce bronchoconstriction in asthmatics but not in normal subjects

# certain components of complement system have activities that may contrbute to allergic reaction

    1) aggregated IgE can initiate alternative pathway in vitro

    2) C3a, C5a induce mediator release from basophil, mast cell

           --> wheal & flare reaction

    3) C2 mediate angioedema in hereditory angioedema

# Anaphylatoxin

    ; *C3a, C5a 말함

    ; chemotactic activity 가지고 있음.

Chapter 134. Diagnosis

General and Specific Method of Diagnosis

Allergy History

Å병력조사의 중요성을 설명하고, 중점적으로 알아보아야할 4가지

; nature of inquiries into possible causes of sympom

    - detailed history fo “exposure” to potential allergens

Seasonal Symptom

    eg) pollen

   perenial Sx eg) houst dust

   house dust mites - house dust에서 allergen

      occurs at the end of summer because high humidity favors  mites proliferation

Relationship Between Symptom And Where They Occur

pollen; outdoor에서 흔함

   allergy to fungi - worsening of symptoms in a damp, musty

Association Between Symptom And Certain Activities

소아에서 strenous exercise coughing or wheezing->asthma

   provocatin of coughing by laughter, crying or exposure to smoke

   or specific odors suggests the bronchial hyperresponsiveness   

   characteristic of asthma

Nature Of Sx

  intermittent recurrent,dry or cough productive clear mucus

 -> asthma

 cf) chronic persistent cough productive purulent sputum

 -> bronchiectasis or cystic fibrosis

Allergic Rhinitis

 -> chronic or recurrent clear nasal discharge

    sneezing or conjunctival itching & injection with excessive   tearing

 Vernal conjunctivitis

-intense conjunctival itching asso. with photophobia and a viscid, white conjunctival     

 discharge

Any Beneficial Or Adverse Effects Of Previous Treatment

이전 치료의 부작용과 advantage 대한 병력 중요

Immediate Fhx

eg) atopic dermatitis

Phsical Examination

1) Height & Weight

2) pulsus paradoxus --acute asthma airway obstruction severity  index.

                       (20mmHg이상->moderate or severe aw obstruction)

                      그외 cystic fibrosis

                      heart failure

                      cardiac tamponade

 

3) cyanosis; SaO2 <85%

4) supraclavicular & intercostal retraction

5) flaring of alae nasi

6) dyspnea

7) mouth breathing

8) allergic shiners - dark discolaration of lower eyelid

9) allergic salute - habitual wiping of the running nose

10)Dennie lines .(Dennie-Morgan folds) - wrinkle beneath the lower  eyelids. all rhinitis,                                           asthma, atopic dematitis

11)digitai clubbing - comparison of the depth of the index finger at  the base of the nail                      with its depth at the distal interphalangeal  joint (Table 134-1)

   normal : depth at the base - smaller

12)Inspection of skin

  atopic dermititis - erythematous maculopapular eruption, fine scaling, or weeping&                           oozing with excoriation due to frequent scratching

  Urticaria lesion - cholinergic urticaria, angioedema, dermographism

  contact dematitis

13) Exam of eye

  allergic conjunctivitis : excessice tesring, periorbital edema

  vernal conjunctivitis : tenacious ropy,mucoid conjunctival discharge

14) nasal mucosa : pale,blue or pink

15) Exam of chest : A-P diameter증가

In Vitro Tests

Total Eosinophil Count

; diurnal rhythm & intermittent

    - highest in the early morning

    - *2-3번의 검사를 해서 eosinophilia 진단한다.

; *more accurate than PBS

; normal - 250-700/mm3

; *in allergic condition, not exceed 15-20%

    - rarely 35% in allergic children

; DDx

    - drug hypersensitivity, rheumatologic disorders, pemphigus, dermatitis herpetiformis, inherited eosinophilia, allergic bronchopulmonary spergillosis, various malignancy(leukemia, lymphoma, Hodgkin disease), eosinophilic fascitis, toxic oil syndrome, eosinophilic-myaligia syndrome(associated with L-tryptophan)

; very high eosinophil count

    - parasitic infection with *tissue-invading helminths(Toxocara, trichinosis, Echinococcus, Ascaris), malaria, hypereosinophilic syndrome

Eosinophilia Of Respiratory Secretion : 의의 설명

; hansen stain - eosin-methylene blue stain

; smear of nasal secretions or bronchial mucus

; *suggest diagnosis

; *allergic rhinitis - 5-l0% eosinophil in nasal secretion

; *bronchial asthma - eosinophil in bronchial mucus

Total IgE Content Of Serum : 진단적 가치

; variable in age

   - Table 134-2

; usually higher than normal

   - DDx 해야 한다. Table 134-1

    - atopy 하여 반드시 증가하지는 않는다.

; *very low level이면 excluding atopic disease

    - atopy 하여도 very low level 수도 있다.

; increased total IgE during infancy

    - suggest the likelihood of subsequent development of atopic disease

Radioallergosorbent Test (RAST)

; Ag.-specific IgE concentrations in serum

; good correlation with medical histories, provocation tests, leukocyte histamine release tests, allergy skin testing

; *less sensitive than skin testing

Leukocyte Histamine Release Test

detect specific IgE Ab. attached to the surfaces of peripheral bl. basophils by measuring the amount of histamine released in response to challenge with Ag.

Histamine분비량은 allergen양에 따라 다르며 cell내의 total histamine percentage 반영.

Skin test sensitive

In Vivo Tests

Skin Testing : 종류, 방법, 특징

; important tool in Dx of IgE mediated sensitivity

# 종류

    ; prick/puncture skin testing

    ; intradermal skin testing

    ; patch skin testing - late phase 검사

# positive intradermal reaction

    ; *at least 5 mm of induration plus surrounding erythema, occuring 15 mm after injection of Ag.

    ; immediate wheal & flare reation peak in 15-30min

    ; *indicate presence of specific IgE Ab on mast cell

    ; *allergen 노출시 반드시 Sx 가진다는 것을 가리키는 것은 아니다.

# *positive puncture skin test correlate better than more sensitive intradermal tests with specific IgE Ab & appearance of clinical symptom

Å위양성과 위음성을 찾은 방법과 이들의 유발 조건

# Pseudopositive

    ; histamine & normal saline control

    ; irritant materials in extracts

    ; improper technique --> nonimmunologic hitamine release

# Pseudonegative

    ; drugs medication

           - adrenergic drug (epinephrine & ephedrine) at least 12 hr withhold

           - antihistamine at least 72 hrs

           - *hydroxyzine for 5 days

           - *astemizole for 2 month

    ; corticosteroid

           - *no appreciable inhibitory effect on IgE-mediated reaction

           - *systemic corticosteroids for 1yr

                   --> suppress cutaneous reactivity to codein(but not to histamine)

                           : suggesting suppresion of histamine release

Provocation Testing

Å실시하는 이유

    ; skin test results clinical sympton on natural exposure 일치하지 않을 경우

    ; 진단이 불확실한 경우

    ; 면역 치료에 사용할 allergen선택을 위해

# 종류

    ; mucous membrane provocation testing

    ; bronchial challenge testing

    ; bronchial provocation testing with methanecholine or histamine

    ; oral provocation test

Chapter 135. Principles of Treatment

# 4 Principle Of Successful Management Of Allergic Disorders

    1. avoidance of allergens or irritants

    2. pharmacologic therapy

    3. immunotherapy (hyposensitization or desensitization)

    4 prophylaxis

# avoidance to house dust mites

    ; *household humidity < 50%

Prophylaxis

; high allergenic potential individuals screening

    - *infants born into families with strong histories of hay fever, asthma. or atopic dermatitis

    - *cord blood IgE level > 1.3 lU/mL, elevated serum IgE levels, eosinophilia during infancy

    -->        recommend breast-feeding for *at least 6 mo

           avoid foods of highly allergenic potential such as eggs, cow milk, wheat, fish, citrus fruit and peanut butter

           nursing mother should avoid highly allergenic foods in her diet

; avoidance of environmental exposure for sensitized & asthma patients

135.1 Pharmacologic Therapy

Adrenergics : 아드레날린 계열의 약물을 분류, 각각의 약리작용 부작용

# α-receptor : excitatory

    ; vasoconstriction

  ; reduces edema of nasal mucous membranes through vasoconstriction & decrease the permeability of venules & capillaries

# α-receptor

  ; alpha 1 - contract vascular & airway smooth m.

    ; alpha 2 -

# β-receptor : inhibitory

    ; bronchodilation, smooth m. relaxation

# β-receptor

  ; beta1 - equal affinity for epinephrine & norepinephrine

  ; beta2

           - 10-fold higher affinity for epinephrine than NE

       - *beta2-selective agonist

                   : isoetharine, metaproterenol, terbutaline, albuterol, fenoterol, bitolterol, pirbuterol, salmeterol

           - *effective bronchodilation in asthma without significant increase in HR

           - *S/E : skeletal m.tremor, glycogenolysis, hypokalemia

# Adrenergic Drug종류

    1) catecholamines

           ; Epi, isoetharine, isoproterenol, bitolterol   

           ; rapidly inactivated by enzymes in GI tract & liver

           ; *limited to injection, inhalation, topical application

    2) noncatecholamines

           ; ephedrine, pirbuterol, procaterol, fenoterol

           ; relatively weak β-stimulant activity, frequently S/E

           ; *S/E - insomia, irritbility, headache

    3) newer noncatecholamines

           ; terbutaline, albuterol, salmeterol, metaproterenol

           ; *relativiely selective activity on β-2 receptors and less cardiovascular effects

           ; longer duration than ephedrine

                   - salmeterol

                           / *very long acting

                           / inhalation of a single dose --> 12hr bronchodilatation

                                   : inhibit both immediate & late-phase reactions

                                   : inhibit allergen induced bronchial hyper-responsiveness

           ; *inhalation lower dose 몇배의 효과와 부작용의 최소화로 가능한한 aerosol administration

# Autoantibodies Against β2-Receptors

    ; asthma, CF, a few normal 에서 발견

    ; ass. with β-adrenergic hyporesponsiveness

           --> tolerance & desensitization

    ; no serious therapeutic implications

# Adverse Side Effects

    ; skeletal m. tremor, cardiac stimulation, worsening of hypoxemia, headache. insomnia, increased airway obst., irritability, nausea, vomiting. epigastric pain, flushing, tolerance(subsensitivity, refractoriness)

# Nebulization에도 불구하고 bronchoconstriction발생할 고려해야

    ; Benzalkonium chloride

           - *preservative in most albuterol & metaproterenol nebulization solutions

           - occasionally bronchoconstriction

           - metered-dose inhalers으로 대치

    ; Metabisulfite

           - stabilizing agents in solution for nebulization

           - bronchoconstriction

Theophylline : 작용기전, 부작용, 투여시 주의사항

; use fo both chronic & acute asthma

# Mode Of Action

    ; adenosine antagonism

    ; effect on calcium flux across cell membrane

    ; prostaglandins antagonism

    ; release of or synergistic interactions with beta adrenergic agonist

    ; enhancement of binding of cAMP to a cAMP-binding protein

# Effects

    1. bronchodilation by relaxing bronchial smooth m.

    2. increases concentration of endogenous catecholamine in the circulation

    3. enhance the contractility of the fatigued diaphragm

    4. inhibit both immediate & late-phase asthmatic response to allergic challenge

    5. sometimes reduce bronchial hyperresponsiveness

# *therapeutic & toxic effect 모두 serum concentration 연관되어 있다.

    ; *serum level of toxic effect - 20 ug/mL 이상

    ; *measurement of serum theophylline concentration

           - *15-min method : excellent result

           - *saliva collection : 60% in serum

Pharmachokinetics

Table 135-1, 135-2

# 종류

    ; rapidly absorbed formula

    ; slow-release (SR) formula

           - TheoDur tablets, Slo-bid Gyrocaps, TeoDur Sprinkle, Uniphyl, Teolair-SR

# *식사에 의한 영향을 받는다.

    ; *RAF no effect

    ; *SRF accelerated or delayed

           - TheoDur tablets or Slo-bid Gyrocaps

                   / peak serum conc. 늦어지지만, no effect on bioavailability

           - TheoDur Sprinkle

                   / 50% bioavailability 감소

           - Uniphyl

                   / double absorption rate

    ; *TheoDur tablets or Slo-bid Gyrocaps 제외한 SRF 식전 60분에 투여하는 것을 원칙

# peak serum concentrations

    ; most SRF 4-6hr after administration

    ; SRF RAF보다 no fluctuations

           - *12hr interval 투여시에는 있을 있으므로 8hr interval 투여를 원칙

Pharmacodynamics

; logarithmic relationship between theophylline bronchodilator effect and serum concentration

    - *5-20 ug/mL

Toxicity

# Symptom & sign of acute intoxication

    ; variable

           - nausea, insomnia, irritability, tremor, headache, seizure & death

    ; Gl symptoms

           - *N/V, hematemesis, cramping

           - *ealiest sign & precede the more serious CNS manifestation

    ; disturbance in cardiac rate

           - tachycardia, arrhythmia(APC, VPC), hypotension

           - *serious toxicity 흔히 나타난다.

    ; hypokalemia, hyperglycemia, ataxia, hallucanations.

# Treatment of intoxication

    ; induce emesis or gavage

    ; *activated charcoal

           - *also remove serum theophylline

           - ipecac 사용할 경우에는 emesis 일어날 때까지 charcol투여를 delay

    ; nonabsorbed saline cathartics

    ; peritoneal dialysis

    ; hemoperfusion using a specially prepared column

           - *method of choice

    ; diazepam for seizure

    ; propranolol for hypotension or supraventricular or ventricular arrhythmia

    ; lidocaine for ventricular tachycardia

    ; ranitidine for gastric acid-induced emesis

# chronic theophylline use

    ; subtle behavioral change

           - hyperactivity & sleep disturbance

         - no adverse effect on congnitive function.

Antihistmine

# 3 Histamine Receptors

    ; H1, H2, H3 receptors

# H1-Receptor Blocker

    ; initially used in treatment of allergic disorders

# *Combination of Hl & H2 Antagonist

    ; beneficial some patients with *chronic urticaria, anaphylactoid reaction(e.g., IV contrast media)

# H2-Receptor Blocker

    ; cimetidine, ranitidine

    ; *inhibit delayed-type hypersensitivity skin response

           --> suggesting modulation of CMI

# Classification : 투여시 주의사항

    1) First Generation Antihistamines

           Type I    - ethylenediamines

           Type II   - ethanolamine 

           Type III - alkylamine

           Type IV - piperazine

           Type V  - piperidines

           Type VI - phenothiazines

    2) Hydroxyzine

    3) Second Generation Antihistamines

           ; *terfenadine, astemizole, loratadine, cetirizine(active metabolite of hydroxyzine)

# 2nd generation antihistaminse 특징

    ; effective suppressing sign & symptoms of allergic rhinitis

  ; do not cross the BBB - less sedative effect

# Antihistamine chemical classification no functional significance

    ; *except) cyproheptadine - antiserotonine activity

# Bioavailability

    ; rapidly absorbed through GI tract

    ; onset of action within 30 min

    ; peak plasma concentration within 1hr

    ; complete absorption within 4hr

    ; mostly metabolized in liver

    ; *little correlation between serum concentration and therapeutic effect in tissue

           - suppressing the wheal & flare response over 24hr

           - chloropheniramine

                   / mean serum half-life of 13.7hr but significant suppression of clincial symptom as long as 30hr

           - *cholorpheniramine, bromopheniramine, hydroxyzine

                   / *twice or even once a day

 more effective in preventing than in reversing the action of  histamine

# Allergy(Asthma)에서 Antihistamine 선택하지 않는 이유

    ; act as competitive antagonists

           - less potent in antagonizing effect of histamine

    ; lung에서 allergic reaction histanine보다는 bronchoconstriction 야기하는 다른 mediator 관련

# *소아에서 asthma course 이롭지도 해롭지도 않다

# Adverse Effects

    1) exocrine secretion

    2) CNS

           ; sedatives

           ; drowsiness

           ; 1st generation 흔함.

    3) cardiovascular system

           ; 1st & 2nd generation 모두 나타날 있다.

           ; prolongation of QT interval, ventricular tachycardia, cardiac arrest

           ; *loratadine 아직 보고되지 않았다.

    4) anticholinergic effect

           ; excitation, nervousness, tachycardia, palpitations, dryness of the mouth, urinary retention, constipation

    5) others

           ; seizures, skin eruptions, blood dyscrasias, fever, neuropathy

# Increased risk for adverse effects

    ; impaired hepatic function

    ; concurrent treatment of inhibitor of cytochrome P450enzyme

           - Erythromycin, macrolide AB, ketoconazole, itraconazole

# antihistamine CNS depressants 병용해서 사용하면 않됨

Cromolyn Sodium (Disodium Cromoglycate)

; disodium salt of 1,3,-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane

; chemical analog of drug khellin

; 투여 방법

    - powder(Intal) with special turboinhaler, Spinhaler

    - 1%(20mg/ml) solution for neubulization

    - metered-dose inhaler(800ug/actuation)

# Indication

    ; *pricipally in asthma for prophylaxis

           - *20mg two to four times each day by Spinhaler or nebulization

           - *1.6mg two to four times each day by metered-dose inhaler

    ; allergic rhinitis

    ; aphthous ulcer, food allergy, systemic mastocytosis, ulcerative collitis, chronic procitis

# Action Mechanism & Effect

    ; *no bronchodilator effect

    ; *no antimediator or antiinflammatory effect

    1) prevent both Ab-mediated & non-Ab-mediated mast cell degranulation & mediator-     release

           ; due to block Ag-stimulated calcium transport across the the mast cell memhrane

           ; due to regulation of phosphorylation of mast cell protein

           ; due to weak phosphodiesterase inhibitor activity

           ; *no effect on basophils or cutaneous mast cells

    2) reduce airway hyperrectivity

           ; unknown mechanism

    3) prevent late-phase asthmatic responses

    4) inhibit bronchocontriction produced by nonimmunologic stimuli

           ; due to directly neural control of airway by inhibiting reflex bronchoconstriction through *inhibition of transmission of neural impulses by myelinated afferent nerve fibers

# *Great Value Of Cromolyn Sodium

    ; allergic or extrinsic asthma

# Side Effect

    ; extremely low incidence

    ; dry throat, transient bronchoconstriction

           - *frequently

           - due to inhalation of dry  powder not intrinsic effect of drug

    ; rare - urticaria, angioedema, pul. eosinophilia

Nedrocromil sodium

antiallergic & antiinflammatory activity 가짐

new agent that inhibit early- & late-phase responses after Ag. challenge

# action

1. inhibit release of mediator from human lung mast cells &    

  supresses activation of neutrophil. macrophage.

2. inhibit bronchoconstrictive effects of exercise

# Adverse effect

  unpleasant taste. coughing, sorethroat,headache,nausea, rhinitis

Lodoxamide tromethamine

:mast cell stabilizer more effective than cromolyn sodium in allergic 

 ocular disease

Ix; 2 이상에서 vernal keratoconjunctivitis, vernal conjunctivitis,

   vernal keratitis.

adverse effect; burning or sttringing

Corticosteroids

; *potent drugs available for treatment of allergic disorder

# bioavailability of prednisone

    ; 80% of oral dose

    ; interconversion to prednisolone(active form)

    ; peak plasma conc. at 1-2hr

    ; little effect of liver disease or renal insufficiency

# bioavailability of prednisolone

    ; effect within 2hr

           - fall in eosinophil. lymphocyte

  ; maybe delaye effect 6-8 hr or longer

           - hyperglycemia, improvement in pul. function in asthamatics

           - reflect the indirect mechanism of action of glucocorticoid

# Step Leading To Activity

    1) simple diffusion through the cell membrane

    2) binding to cytosol glucocorticoid receptors

    3) translocation of the steroid-receptor complex to the nucleus

    4) binding of the complex to chromatin, which affects nuclear gene expression

    5) subsequent synthesis of messenger RNA & protein with enzyme activity

# phenobarbital & phenytoin

    ; increase steroid clearance

# Anti-Inflammatory Actions Of Glucocorticoids Result From

    1) alteration in leukocyte number & activity

           ; redistribution

           ; suppression of migration to sites of inflammation

           ; decreased response to mitogens

           ; decreased cytotoxicity

           ; suppression of delayed hypersensitivity responses in the skin

    2) surppression of mediator release

           ; decreased histamine synthesis & release

           ; decreased synthesis of prostaglandine & other product of arachidonic acid metabolism

    3) enhanced response to agents that increase cAMP

           ; PGE3, histamine via H2 receptor

    4) enhanced response to catecholamine

           ; increased systhesis of beta-adrenergic receptor

         ; increased availability of epinephrine due to decreased extraneuronal uptake of catecholamine

# chronic administration

    ; reduce total Ig concetration

Topical steroid

; direct local effect

    - decreased inflammation, edema, mucus production, vascular permiability & mucosal IgE level

    - less accumulation of neutrophil, eosinophils, basophils, mast cells

    - attenuation of airway hyper-responsiveness

; reduce early-& late-phase reaction

    - *systemic steroid late-phase eaction 주로 inhibition

# Complication of Inhaled steroid

  ; oropharyngeal candidiasis, dysphonia

    ; suppression of H-P-A axis at high dose

# Growth Impairment

    ; more than 400ug at total daily dose

    ; *depend on dosage and duration

    ; possible normal height after discontinuation

4) long-term use Cx

 - mc adverse effects: suppression of linear growth

 - Post. subcapsular cataracts

 - osteoporosis, hypertension, DM, cushingoid habitus, infection(disseminated varicella or     Pneumocystis carinii),pancreatitis, gastritis, myopathy.

# Considerations In The Systemic Use Of Corticosteroids

    1) when given in equivalent anti-inflammatory doses, available drugs *do not differ qualitavely in anti-inflammatory effects

           ; adverse effects are related to dose, dosing interval. & duration of treatment

           ; oral administration

                   - predenisone, prednisolone

           ; iv administration

                   - methylprednisolone, hydrocortisone

    2) when corticosteroid therapy is initiated, *sufficient amount should be given in 3-4 divided doses to bring the disease under control

           ; whenever possible, alternate-day regimens using 

                   - prednisone & prednisolone every 48hr

                   - single dose between 6:00 and 8:00 a.m.

           ; adult data

                   - single dose at 3:00 p.m.

                   - better control of asthma esp. nocturnal asthma

    3) short-term steroid therapy (<7 days) suppress the pituitary-adrenal axis only briefly and *can be stopped abrouptly without tapering dose

Additional Pharmacologic Agents

(1) anticholinergic agent having antimuscarinic activity

   adjuvant aerosol therapy 이용

   atropine sulfate, ipratropium bromide

   bronchodialtor effect - not as great as sympathomimetic agents

(2) ketotifen, benzocyclohepatathiophine

   antihistamine with mast cell-stabilizing  property

   leukotriene  antagonism

   inhibit IgE-dependent medidator release.

   attenuate platelet activating factor-induced bronchoconstriction

(3) calcium channel blocking agent, nifedipine

   block bronchoconstriction due to allergy, exercise, PGF2, LT C4 & D4, cold air,    

   histamine, methacholine

(4) methotrexate

135.2 Immunotherapy

Immunologic Change

1) appearance of Ab of the lgG class

    ; blocking or Ag-binding Ab

    ; ultimate titer is related to the quantity of extract injected

           - but does *not correlate with clinical change

2) *inhihit histamine release from leukocytes (basophils)

    ; “desensitized”

    ; unknown basis

    ; *not related to titers of Ig E or Ig G

3) change in ratios of helper to suppressor T cell

    ; *increase in antigen-specific suppressor T-cell

4) inhibit the late-phase asthmatic response

Studies Of Efficacy

# 고려해야 할점

    ; cost of immunotherapy

    ; inconvenience

    ; the possibility of the disease worsening

    ; the risk of inducing anaphylaxis

# ★효과가 인정된 Allergens

    ; *ragweed, grass, tree pollen, house dust mite, Alternaria, maountain cedar, Clasdosporium, cat allergen

# 효과가 인정되지 않은 allergens

    ; danders (dog, horse), most molds, bacterial vaccines, occupational allergens, synthetic Ag, whole-insect extracts, food extracts

# *multiple allergen 가진 경우에는 not effective

Indications, Materials, And Procedure

# Indication 

    1) allergic rhinitis

  2) IgE-mediated asthma

  3) allergy to stinging insect

# *atopic dermatis & food allergy not effective

# Candidate For A Trial Of Immunotherapy

  ; good correlation between symptom and inhalant allergen that cannot be avoided

    ; evidence o IgE-mediated allergy

    - either skin test or in vitro test

  ; disabling symptom are not easily controled with medication

# Extracts

    ; *common used extracts - aqueous extracts

    single injection 1O가지 이내의 allergen 포함되어야

          high-dose therapy allergen 수가 적을때 효과적

          children tolerate the same doses as adult

# failure to see a local reaction at any time 의미

  1. the pt. is not allergic to the constituents of the extract

  2. the extract is inactive

# Procedures

    1) conventional methods

    2) “rush” methods

    3) perennial methods

# Beneficial Results

    ; *6개월 이후에 나타남

# Duration Of Treatment

    ; *치료후 3년동안 의미있는 증상의 호전을 보이면 치료를 중단할 있다.

    ; *치료를 계속해도 2년내 증상의 호전이 없는 경우에는 치료를 중단해야 한다.

Precaution And Adverse Reactlons

; *obsevation for at least 20min after each injection

; *no short- or long-term adverse effects except for consitutional symptoms

Respiratory Allergy

respiratory tract - most frequently affected by allergic disorders during childhooa

Chap 136. Allergic Rhinitis

# seasonal allergic rhinitis, seasonal pollinosis,& hay fever

- a symptom complex seen in children who have become sensitized    to wind-borne pollens of trees, grasses, & weed

# increasing prevalence with age

# ragweed hay fever is rare before 4-5yr

# perennial allergic rhinitis

# *Indoor Inhalant Allergens

    ; *often

    ; house dust, feathers, allergens or danders of household pets, mold spores

# Prognosis

    ; not good

    ; *only 10% symptom free after 8-11 yr

    ; *19% asthma or wheezing

Pathophysiology

Ag. are deposited on the nasal mucosa

- water-soluble Ag. diffuse into the epithelium

- in genetically predisposed atropic individual, initiate the production   or local IgE

- IgE stimulated release of mast cell mediators, synthesis of new  mast cell mediators

- subsequent recruitment of neutrophil, eosinophil. basophil, &   lymphocyte

- early & late-phase reaction

- mucus, edema, inflammation, pruritus & vasodilation

delayed inflammation: nasal hyperresponsiveness to nonspecific stimuli야기

Diagnosis

# symptoms & signs

    ; paroxysmal sneezing

    ; watery & profuse rhinorrhea

# Local Findings

    ; bilateral nasal obstruction due to boggy edema of the membrane

    ; redundant mucosa is piled up on the floor of the nose

    ; bluish mucous membrane

    ; clear nasal discharge

# itching of the nose, palate, pharynx & ears

# eye

    ; itching, redness, tearing -- causing severe symptoms

# Characteristic mannerisms

    ; *rabbit nose & allergic salute

    ; *allergic shiner

           - dark circles under the eyes

           - due to venous stasis result from edematous nasal mucous membrane

    ; mouth breathing

# *fever - bacterial sinusitis, otitis media합병시

# nasal smear

    ; best prepared

    ; eosinophilis

Differential Diagnosis

1. eosinophilic non-allergic rhinitis

  adult common

  serum IgE - normal, skin test - negative

2. primary nasal mastocytosis

  perennial nasal blockage & rhinorrhea

  mast cell in smear, skin test - negative

3, neutrophilic (infectious) rhinitis

 early years of childhoodo  common

4, vasomotor rhinitis

5 기타  nasal obst. 야기하는 원인

unilat. choanal atresia, septal deviation, adenoidal hypertrophy encephalocele, nasal polyposis

 -  in ciliary dyskinesia, immunologic deficiency

# Triad asthma : syndrome of nasal polyp. asthma. & aspirin intolerance

foreign body : foul-smelling, unilat. purulent or blood-tinged    

              purulent nasal   discharge

malignancy : persistent bloody nasal discharge

# benign nasopharyngeal fibroma (angiofibroma)

    ; nasal obst. with epistaxis in late childhood or early  early adolescence

Treatment

1. avoidance of exposure to suspected allergens or irritants

2. immunotherapy who can't avoid inhalant allergens

3, drug therapy

Avoidance

Drug Therapy

# Antihistamines

    ; useful in seasonal allergic rhinitis

  ; nasal itching, sneezing, & rhinorrhea : well controlled

    ; *use nonsedating antihistamines (astemizole, loratdine, terfenadine)

# Decongestant

    ; troublesome nasal obstruction있을때 사용

    ; pseudoephedrine, phenylpropranolamine

           - alone or combination with antihistamines

           - short-term use

    ; 97 decongestants 장기간 사용시 생기는 질환과 치료법

           - rhinitis medicamentosa

         - progressively severe nasal obstruction due to rebound vasodilation

           - Treatment

                   / complete cessation of use medicated nose drops

                   / substitution of mose drops of physiological saline solution

# Cromolyn Nasal Solution

  useful in both perennial &  seasonal allergic rhinitis

  prophylactically

# Corticosteroid

    ; *effective as topical use

    ; beclomethasone(vancenase or beconase) budesonide(rhinocort), flunisolide(nasalide), fluticasone(flonase)

    ; used in resistant to antihistamine-decongestant therapy

    ; no systemic absorption, candidiasis & mucosal atrophy are not  problem

* persistent neutrophilic (infectious) rhinitis

- 2 WK course of broad-spectrum AB.(amoxicillin)

   nasal irrigation - with Water Pik device

Chapter 137. Asthma

; *frequent admitting diagnosis in children

# Incidence

    ; 10-15% of boys and 7-10% of girls during childhood

    ; before puberty        - male 2

  ; after     "           -  same

# Definition

    ; diffuse, obstructive lung disease with

           1) hyperreactivity of the airways to a variety of stimuli and

           2) a high degree of reversibility of the obstructive process, which may occur either spontaneously or as a result of treatment

# reactive airway disease

    ; wheezy bronchitis, viral-associated wheezing, & atopic related asthma

# alternative designation

    ; chronic desquamating eosinophilic bronchitis

# hyperresonsiveness

    ; bronchoconstriction after exposure to exercise, strong odor or irritant fumes (sulfur dioxide, tabacco smoke, cold air & histamine, parasymptomatics ( eg.methacoline) 

# acute decrease in airway irritability

    ; beta-receptor agonist, theophylline, anticholinergics, cromolyn, steroid

# inheritance

    ; *one affected parent : 25% risk

    ; *both  "       "     :   50% risk

    ; *not universally present amon monzygotic twins

Epidermiology

# onset

    ; 30 % of pt : 1

  ; 80-90 % pt : 4 ~5 이전

    ; relationship of age of onset to Px :uncertain.

# Most Severely Affected Chiidren

    ; *wheezing onset during the 1st yr of life, family history of asthma, other allergic diseases esp. atopic dermatitis

    ; steroid 투여와 관계없이 growth retardation (+)

    ; 지속적인 PFT이상

# Prognosis

    ; generally good

  ; depend on growth in the cross-sectional diameter of the airway

    ; *50% of asthmatic children

           - *free of symptom within 10-20 yr

           - common recurrence

miId asthma with onset between 2yr & puberty

 : remission rate 50% & 5% develop severe dis,

severe asthma : 95% become adult asthmatics

과거 20 동안 asthma 빈도와 mortality 증가

# Risk Factor For Occureance Of Asthma

    1) poverty, black race

    2) *maternal age <20 yr at birth

    3) BW < 2500gm

    4) maternal smoking

    5) small home house (<8 roomes)

    6) large family size (> 6 members)           

    7) intense allergenic exposure in infancy

    8) frequent URI in childhood

# Risk Factor For Death From Asthma

    1) underestimation of the severity of the illness

    2) delay in implementation of appropriate treatment

    3) underuse of bronchodialtor & steroid

    4) black race

    5) noncompliance with recommendations for treatment

    6) Psychosocial dysfunction & stress

    7) sedation

    8) excessive allergenic exposures

# ★▲high risk for fatal astma

    ; *sudden, severe airway obstruction

    ; *chronic steroid-dependent asthma

Pathophysiology

# Airway Obstruction In Asthma Are Due To

    1. bronchoconstriction

    2. hypersecretion of mucus

    3. mucosal edema

    4. cellular infiltration

    5. desquamation of epithelial & inflammatory cell

various stimuli

- inhaled allergens: dust mite, pollen, soybean or caster bean

  protein

  vegetable protein

  viral infection

  cigarette smoke

  air pollutants

  odors

  drugs: NSAID, beta-receptor antagonists, metabisulfite. tartrazine

  cold air

  exercise

# pathology of severe asthma

    ; bronchoconstriction, bronchial smooth m. hypertrophy, mucus g1. hypertrophy, mucosal edema, infiltration of inflammatory cell, desquamation

# pathognomonic findings

    1. Charcot-Leyden crystals (eosinophil membrane)

    2. Curschmann spirals (bronchial mucus cyst)

    3. Creolar bodies (desquamated epithelial cells)

# immune responses

 early - result in bronchoconstriction

        treatable with beta2-receptor agonists

        maybe prevented by mast cell stabilizing agent (cromolyn)

 late - occurs 6-8 hr later, produce a continued state of airway

       hyperresponsiveness with inflammatory cell infiltration

       treated &  prevented by steroids

prervented by cromolyn

Pathophysiology. (Fig. 137-1)

 Obstruction : most severe during expiration

    -> hyperinflation

    -> decreased compliance

    -> increased work of breathing

       & * increased transpulmonary pressure.

       -> further narrowing & premature closure of some aw.     

          during  expiration

      & * increased intrathoracic pressure-> venous return방해

       ->  C.O 감소 ->pulsus paradoxus.

-> mismatching V/P

    ->alveolar hypoventilation.

    -> PaO2감소, PaCO2증가

    -> metabolic & respiratory acidosis

acidosis & hypoxia->pul. vasoconstriction

-> damage to Type II alveolar cell.

-> atelectasis 유발.

Etiology

# *astham is a complex disorder involving autonomic, immunologic, infectous, endocrine, psychologic factors varying degrees in different individuals

# Control Of The Airway Diameter

    ; balance of neural & humoral forces

    ; neural factor

           - bronchoconstriction

                   / vagal sensory ending

         - bronchial m. relaxation    

                   / *vasoactive intestinal peptide(VIP)

                           : *dominant neuropeptide in maintaining airway potency

    ; humoral factor :

         - bronchodilation - endogenous catecholamine acting on β-receptor

         - bronchoconstriction - histamine,leukotrienes, locally produced adenosine

# 89 Szentivany theory

    1. abnormal β-adrenergic receptor-adenylate cyclase fuction with deceased adrenergic responsiveness.

    2. hyporesponsiveness to β-agonist

           ; deceased number of β-adrenergic receptors on leukocytes

    3. increased cholinergic activity in the airway

Immunologic Factors

Å병인론적인 분류

# Extrinsic or Allergic Asthma

    ; follows exposure to environmental factors

  ; increase of total IgE & specific IgE against allergen

# Intrinsic Asthma

    ; clinically similar asthma

  ; no evidence of IgE involvement

           - low level of IgE, negative skin test

    ; *often 1st 2yr of life and in older adult (late-onset asthma)

# viral agents

    ; *important infectious triggers of asthma

        - through stimulation of afferent vagal receptor of cholinergic system

    ; *early in life - respiratory syncytial virus & parainfluenza virus

           - RSV respiratory disease no wheezing

    ; *older chiId - rhinovirus

    ; influenza virus - important with increasing age

Endocrine Factors

 worsening - pregnancy, menses, esp, premenstrually or maybe at                

             menopause, thyrotoxicosis

 improving - at puberty

Psychologic Factors

 emotional  or behavioral disturbances asthma attack severity   다는 poor control 관련

Clinical Manifestations

    ; attack

  acute episode : by exposure to irritants, allergens or   

                  simple chemicals

                 due to smooth m. spasm in large airway

  slower onset : by viral respiratory infection

  at night: airway patency 가장 감소하므로 attack 일어남

    ; cough : nonproductive early in the course of attack

wheezing : extreme resp. distress 없을 있음

tachypnea & dyspnea uith prolonged expiration:hunched

 -over. tripod-like posture

use of accessory m. of respiration : abd. m. 사용시  abd.  pain complaint

cyanosis

hyperinflation of chest

barrel chest deformity : a sign of chronic, unremitting  airway obst. of severe                           asthma

    ; clubbing of finger

           - rare

           - *suggest other cause of chronic obst. lung dis. such as cystic fibrosis

tachycardia & pulsus paradoxus

low grade fever, fatique

Harrison sulci - recurrent sever retraction으로.

Diagnosis

# highly suggestive signs

    ; recurrent episodes of coughing & wheezing

           - esp. if aggrevated or triggered by exercise, viral infection, inhaled allergens

# insufficient flow rate, mild airway obstruction, unrecognizable caretakers

           --> persistent coughing without history of wheezing

    ; PFT 실시함으로 진단에 도움이 된다.

           - before and after methacholine or bronchodilator

           - before and after exercise

# improvement following bronchodilator therapy 진단에 도움이 된다.

Laboratory Evaluation

1) eosinophilia of the blood & sputum

    ; blood eosinophilia

           - more than 250-400 cells/mm3

    ; sputum

           - eosin-methylene blue stain : numerous eosinophil

2) IgE level

3) allergy skin test

4) RAST(radioallergosorbent test)

5) inhalation bronchial challenge test

    ; skin testing 의한 allergen 대해 임상적으로 의심스러울때에만 실시한다.

           - 이유

                   / provoke late-phase asthmatic response

                   / procedure is time consuming

                   / only single allergen is tested

6) methacholine provocation testine

    ; asthma 진단이 의심스러울때

    ; *metachoiline or histamine bronchoconstrictive effect 대한  hyperresponsiveness test

    ; abnormal baseline pul. function 금기

7) exercise test

    ; *characteristlc response against exercise

           - running for 1-2 min : often cause bronchodilation

           - prolonged strenuous exercise : bronchoconstriction when breathing dry, cold air

    ; Treadmill running at 3-4miles/hr up a 15% at least 6min

           --> airway obstruction in mostly asthma

    ; measurement of PFT before & after exercise

           - decrease PFR or FEV1 of at least 15%

    ; withhod drugs

           - bronchodilator & cromolyn : 8 hr

           - theophylline : 12-24 hr

8) Roentgenogram of the chest

  ; exclusion위해 필요

    ; hyperinflation.

    ; atelectasis : 6%, esp. Rt. middle lobe

    ; indication of repeated chest roentgenogram during exacerbation

           - fever

           - peumothorax 의심시

           - tachypnea greater than 60 beats/min

           - tachycardia of more than 160 beats/min

           - localized rales or wheezing, or decreased breath sounds

9) pulmonary function test

    ; useful in

           1) assessing the degree of airway obst. & the disturbance in gas exchange

           2) measuring response of the airways to inhaled allergen & chemical or exercise (bronchial provocation test)

           3) assessing the response to therapeutic agents

           4) evaluating the long-term course of the disease

    ; *valuable when made before & after administration of aerosol bronchodilator

           - *aerosol therapy PFR or FEV1 최소 10%이상 증가시 asthma 강력히 의심

Table 137-1

    ; increase : TLC. RV,FRC

    ; decreaes : VC, FVC, FEV1, PFR, FEF25-75

10) determination of arterial blood gas & pH

Differential Diagnosis

1. congenital malformations (of the resp. cardiovascular, GI systems)

2. foreign bodies in the airway or esophagus

3. infectious bronchiolitis

4, cystic fibrosis

S. immunologic deficiency diseases

6. hypersensitivity pneumonitis

7, allergic bronchopulmonary disease

8. rare condition

    ; endobronchial Tbc, fungal dis., bronchial adenoma

Table 137-2

Asthma In Early Life

; Symptoms of obstructive airway disease

    - 30% younger than 1yr

    - 50-55% younger than 2yr

; 89 antomic & physiologic pecularities of early life predispose to obstructive airway disease

    1) decreased amount of smooth m. in the peripheral airways

           --> less support

    2) mucous gl. hyperplasia, increase intraluminal mucus production

    3) disproportionately narrow peripheral airway up to 5yr

       --> decrease conductance & vulnerable to dis. affecting the small airway

    4) decreased static elastic recoil of the young lung

       --> early airway closure & mismatching ventilation & perfusion and hypoxemia

    5) highly compliant rib cage & mechanicallly disadvantageous angle of insertion of diaphragm to rib cage(horizontal).

           --> increase diaphragmatic work of breathing

    6) decreased numbers of fatigue-resistant skeletal m. fiber in the diaphragm

           --> poorly maintain high work output

    7) deficient collateral ventilation with the pores of Kohn & the Lambert canals deficient in numbers & size

# bronchiolitis

 asthma Clinical, roentgenographic, blood gas finding 유사.

 DDx 1. RSV 의해 생후 6개월에 peak 득히 cold weather months

      2. 2, 3 재발은 드물다.

      3. epinephrine 대한 반응 : favorable response in asthma

      4. onset of Sx typical

        previously well infants or young children

        cold, rhinorrhea, irritability, cough, tachypnea, wheezing,

        Sx 빨리 progress.

# Infancy에서 asthma 감별할 질환

1. resp. infection with virus or chlamydia

   bacterial inf. rare

2. cystic fibrosis or immunologic deficiency

   child with recurrent episode of coughing & wheezing asso. with bacterial inf. 있는

  경우 반드시 검사 .

3. chronic aspiration due to swallowing dysfunction or   gastroesophageal reflux

4. obliterative bronchiolitis

5, bronchopulmonary dysplasia

Food allergy obst. Sx.과의 관계는 controversial하고 positive skin test for IgE-mediated sensitivity to food  unusual하지만 의심스러운  food 일시적으로 제거

  ->3주뒤 challenge :confirm  Food allergy 적어도 6개월간 제외

# Important predictor of subsequent obst. airway problems

1. several episode of obst. airway disease

2. Hx of asthma, hay fever, or atopic dermatitis in family

3. eczem

4. eosinophilia greater than 400 cells/mm3, esp 700 cell/mm3이상 & high serum IgE         conc.

Treatment

# Basic consepts

    ; avoiding allergens

    ; improving bronchodilation

    ; reducing mediator-induced inflammation

Fig. 137-2 ~ 137-4

Avoidance

    ; nonspecific irritants

           - tobacco smoke, smoke from woodburnig stoves, fumes from kerosene heaters to strong odors such as wet paint and disinfectants

    ; icecold drinks, rapid changes in temperature & humidity

    ; humidity not exceed 50%

Pharmacologic Therapy

; *mainstay of treatment of asthma

; O2 supply by mask or nasal prongs at 2-3L/min

; epinephrine

    - *0.01 ml/kg of the aqueous of the 1:1,000(1mg/ml)

    - repeat once or twice at interval 20min

    - upper limit 0.3 ml

; terbutaline

    - selective beta2-agonist,

    - *0.01 ml/kg of the aqueous of 1:1,000(1mg/ml)

    - no peripheral vasoconstriction, longer duration up to 4hr

    - upper limit 0.25ml

; inhalation of bronchodilator aerosol

    - *rapid effective

    - 90,94 장점

           / less drug is given than would be required by the subcut. route

         / unpleasant side effect of injected drug s are avoided

         / more effectve than epinephrine in reversing bronchoconstriction despite airway obstruction

    - albuterol (ventolin)

           / a dose of 0.15 mg/kg (max. 5 mg),

           / 0.05-0.15mg/kg repeat at interval 20-30min until response is adequate

           / available as 0.5% solution (5mg/ml) with 2-3ml normal saline

           / nebulization with oxygen at 6 L/min

; Aminophylline

    - epinephrine or bronchodilator aerosol ineffective 사용.

    - *a dose of 5mg/kg for 5-15min but no more than 25mg/min

    - *dose of 1mg/kg increase serum level by about 2ug/ml

  - beta2-aerosol therapy 병행

           / little additional benefits

           / helpful in severe airway obstruction, less than maximal treatment with inhaled β2-adrenergic agonists

; steroid

    - indication

           / corticosteroid dependent case

           / corticosteroid in recent past

    - borderline cases

           / 입원하지 못하고 귀가를 해야하는 환아의 경우를 말함

           / prednisone decreasing dose over 5-7days 처방

    - reduce the relapse & hospitalization rates

; relapse

    - 15-20% hospitalized

    - *10-20% relapse within 10days

Status Asthmaticus

; clinical diagnosis

    - continuous state having significant respiratory distress despite treatment

    - *increasingly severe asthma that is not responsive to drugs that are usually effective

Table 137-3 Factors associated with risk of severe statrus asthmaticus

92 Treatment

; ICU care

; carefully minitoring

    - bseline CBC & electrolyte

  - cardiac monitoring

    - ABGA

# Oxygen supply

    ; *continuously by nasal prong or mask

    ; 2-3 L/min

  ; *optimal oxygenation

           - *PaO2 : 70-90 mm Hg, SaO2 > 92%

    ; mist tent - should not be used

# Fluid & Electrolyte Balance

  ; cause of dehydration

           - inadequate fluid intake

    - insensible water loss due to tachypnea

    - diuretic effect of theophylline

    ; *no more than 1-1.5 times maintenance level

    ; *Indication Of Bicarbonate

           - arterial pH < 7.3

           - metabolic acidosis

           - serum Na < 145 mEq/L

           --> 1.5-2 mEq/kg, every 4-6 hr

    ; β2-adrenergic agents 사용으로 hypokalemia 초래 있으므로 potassium add.

# bronchodilator sympathomimatic aerosol therapy

    ; continued

# aminophylline

  ; 4-5 mg/kg lV over 20 min, every 6 hr

        or 5 mg/kg IV loading, followed by constant infusion in a dose of 0.75-1.25 mg/kg/hr

    ; TDM

           - *steady state 12-15 ug/mL

           - if every 6-hr regimen

                   / 1 hr after IV injection & just before the next dose

           - if constsnt infusion

                   / 1, 6, 12, 24 hr as a basis for dose adjustment

                   / 6, 12hr after any change dosage

                   / every 24hr while iv theophylline

  ; different starting dose at age

           - 0.5mg/kg/hr at 1-6mo

           - 1mg/kg/hr at 6-11mo

           - 1.2-1.5 mg/kg/hr at 1-9yr

           - 0.9 mg/kg/hr over 10yr

# Terbutaline

    ; 0.01 mg/kg(maximum 0.3mg) sc

    ; 10 ug/kg bolus, 0.4-0.6 ug/kg/min continuous infusiion increasing by 0.2ug/kg/min to 3-6 ug/kg/min) iv

# treatment with antimuscarinic such as atropine suifate

    ; combination with nebulized beta-agonist

           - more effective than alone

# ipratropium bromide : nebulization

# Corticosteroid

    ; *methylprednisolone(solu-medrol) 1-2mg/kg every 6 hr

    ; 87 Effect

           - improve oxygenation

    - decrease airway obst.

    - shorten the time needed for recovery

# mechanical ventilation

  ; volurne-cycled ventilator with short inspiratory & long expiratory times, 10- to15-mL/kg tidal volume, 8-15 breaths/min,

    ; peak pressure 60 cm HzO

  ; goals : 1. improve oxygenation

        2. maintain PCO2 between 40-60 mm Hg

        3. avoid barotrauma

    ; recovery phase, PEEP to prevent atelectasis

    ; sedation of non-ventilated pt : should be avoid

Daily Management Of The Asthmatic Child

Mild Asthma

    ; exacerbations

           - up to twice each week

    ; decrese of PEFR

           - not more than 20%

    ; not severe & respond to bronchodilator treatment within 24-48hr

    ; *medication is not required between attack

    ; good school attendance, good exercise tolerance

    ; no hyperinflation of chest, CXR - essentially normal

    ; PFT - mild, reversible airway obst.

Moderate Asthma

    ; more frequently than mild asthma

    ; cough & mild wheezing between more severe exacerbation

    ; impaired school attendance, diminished exercise tolerance

    ; lose sleep at night, esp. during exacerbation

    ; medication

           - *continuous bronchodilator therapy

           - *continuous treatment with cromolyn, nedocromil or inhaled steroid to reverse bronchial hyper-responsiveness

Severe Asthma

    ; daily wheezing & more frequent & more severe exacerbation

    ; recurrent hospitalization

    ; interrupted sleep by asthma, poor excercise tolerance

    ; chest deformities due to chornic hyperinflation

    ; bronchodilator treatment required continuously & regular systernic or aerosol of steroid

Treatment

Children With Miid Asthma

    ; should receive bronchodilator medication only when symptomatic.

    ; satisfactorlly with adrenergic drug, preferably by aerosol.

    ; theophylline may be added.

 when indicated

* Exercise-induced asthma

   prevented by inhalation of adrenergic drug immediately before  

   exercise -most effective

   inhaldtion of cromolyn or nedocromil

Children With Moderate Asthma

    ; two inhalations of adrenergic aerosol every 4-6 hr or two inhalations of salmetrol every 12hr

    ; theophylline may be added

         - begin with 14-16 mg/kg/24hr : safest

    ; cromolyn powder inhaled 4 times a day from a Spinhaler or cromolyn aerosol

    ; nedocromil

    ; steroid

           - early use on symptom onset

           - 1-2 mg/kg/24 hr, discontinue as quickly as possible

Children With Severe Asthma

# steroid alternate-day basis

    ; steroid alternate-day therapy

           - intense daily therapy : short-acting steroid(prednisone,prednisolone) for 5-7days

                   --> and then alternative -day regimen

           - 12yr-old boys

                   / 60mg, 40mg, 30mg, 20mg, 10mg /24hr over 5days

                           --> 20mg/24hr alternate-day at 6:00-8:00am

                           --> reduced by 5mg/dose at 10-14days interval

                           --> usually 5-10mg on alternate-days

    ; *concurrent therapy with aerosol adrenergic drug, theophylline, or cromolyn

# Inhalational Corticosteroids

    ; *alternative to use of oral corticosteroids

    ; aerosol more effective than oral steroid

    ; beclomethasone

 

# Various factors may exacerbate asthma or rnake the disease

  difficult to treat :

1. gastroesophageal reflux

2. allergic bronchopulmonary aspergillosis

3. nonsteroidal antiinflammatory agents

4. pregnancy

5. sinusitis- treatment with antibiotics, intranasal steroid, & oral or  topical decongestant

           for 3 wks

          -> may improve bronchoconstriction as well as sinusitis

# Prevention of Death from Asthma

   reasons for increase in mortality

1. increased prevalence of asthma

2. increased indoor air pollution, emphasis on energy conservation

3. delay in implementation of appropriate treatment for acute    

  asthma

4. lack of access or utilization of medical care, including preventive  care

5. over-reliance of bronchodilator inhalers leading to delayed treatment with steroids or      other therapy

6. unavailability of epinephrine for pt unable to use inhalers   effectiveiy

7. inappropriate use of the metered dose inhaler & failure to provide  contnuity of care

  or education

# 사망을 초래할 있는 위험인자.

1. resp. failure with hypercarbia

2. loss of  consciousness due to asthma

3. psychosocial dysfunction in the pt or family - judgement &  compliance 장애

Chater 138. Atopic Dermatitis (=Infantile or Atopic Eczema)

; inflammatory skin disorder characterized by erythema, edema, intense pruritus. exudation, crusting, scaling

    - acute stage : intraepidermal vesiculation (spongiosis)

; subsequently to develop allergic rhinitis & asthma

Immunologic Abnormalities

    # increased serum IgE conc.

           ; 80% of patients

           ; 5- to 10- fold

           ; *related to severity or extent of dermatitis

           ; not always increased in affected patients

           ; maybe related to *deficiency of IgE isotype-specific suppressor T-cell function

    # high rates of spotaneous basophil histamine release

    # 82 impairment of cell-mediated immunity

           ; absence of the reaction of delayed hypersensitivity upon intradermal skin testing with certain testing

           ; inability to be sensitized with potent contact sensitizers

           ; diminished proliferative response of lymphocytes to mitogens (e.g. phytohemagglutinin)

           ; variable phagocytic & chemotactic defects of monocytes & neutrophils

# Hyperreactive Skin Of Atopic Dermatitis

    ; white dermographism

         - light mechanical stroke

                   --> within *1 min in a white line with a surrounding blanched area

    ; abnormal rates of cooling & warming in response to temperature change

         - particularly in flexural areas

    ; paradoxical response occur to injection of various pharmacologic agents such as histamine, acetylcholine, nicotinic acid ester

           - *blanching rather than erythma

    ; 원인

           - autonomic imbalance 생각함

                   / 그이유는 decreased adrenergic response in lymphocytes & granulocytes

Clinical Manifestation.

; 2-8% of children

; typically occurs in 3 stages with fairly distinctive features

    - 1 : 생후 2개월에서 2

    - 2 : 2년에서 10

    - 3 : 사춘기와 성인

In Infancy

; *often

; usually during the first 2-3 mo of life

    - sometimes delayed until 2nd or 3rd yr

    - 60% by 1yr, 90% by 5yr

; earliest lesion

    - erythematous weepy patches on the cheeks

        with subsequent extension to remainder of the face, neck, wrist, hand, abdomen, extensor aspects of extremities

; erythmatous flush

    --> marked pruritus

    --> *scratching : major role of production of typical skin lesion

    --> weeping & crusting

    --> secondary infection

; *coincides with introduction of certain foods, esp. cow's milk, soy, peanuts, fish, egg

    - 50-90%

    - 20-30% hypersensitivity to one or more of six common allergens

During Childhood

; remission at 3-5yr

; mostly less prominent by 5 yr

; in some, mild to moderate eczema in antecubital and popliteal fossae, on wrist, behind ears, on face & neck

; after 5yr

    - *common involvement of antecubital and popliteal

    - extensor surf. maybe involved

; with increasing age, drying & thickening of the skin

; mask of atopic dermatitis

    - whitish hue as increased capillary permeability

    - edema & blanching of surrounding tissue due to dilatation

# ★▲Poor Condition

    ; *severe dermatitis, family histories of atopic dermatitis, associated asthma or allergic rhinitis, onset before 1yr, in female

Diagnosis

support Dx

  -increased pruritus & characteristic lesion

  -Family history of asthma, hay fever, or atopic dermatitis

  -elevated serum IgE conc. & reaginic Ab. to a variety of foods &     inhalants

  -eosinophilia

  -demonstration of white dermographism

Table 138-1

Table 138-2

Differential Diagnosis

1) Seborrheic Dermatitis

  - cradle cap : typically begin on the scalp

    - eyebrow and eyelids with greasy

  - *shorter course & respose much more rapidly to treatment

2) scabies

  - location 으로 감별

           / begin with large papule on the upper back  with vesicle on the palm & sole

3) primary irritant dermatitis

4) allergic contact dermatitis

5) infectious eczematoid dermatitis

6) ichthyosis

7) PKU

8) acrodermatitis enteropathica

9) histiocytosis X

10) primary immunologic deficiency dis.-Wiskott-Aldrich syndrome

                                    X-linked agammaglobulinemia

Complicatlons

1) Secondary Infection

    ; bacterial or viral

    ; staphylococcus & beta-hemolytic streptococci

           - Å▲common bacteriae

  ; herpes simplex virus

           - *Kaposi varicelliform eruption

    ; common wart

    ; molluscum contagiosum

2) keratoconus d/t rubbing of the eyelid

3) cataract - *rare in childhood

Treatment

# control of environmental precipitants of itch-scratch-itch cycle

    ; avoidance of ingestant, injectant, contactant(wool) & atmospheric factors

           - avoidance of extreme termperature

                   / warm climate & moderate humidity : optimal

           - avoidance of sweating

                   / exposure to sunlight & salt water : of benefit

           - avoidance of wool

                   / smooth-textured cotton

           - avoidance of soap & detergent

                   / bath oil & other creams

                   / soaking in tepid water for 30min two or three times each day followed by gentle drying and application within 3min of ointment base(Aquaphor) or cream base(Acid Mantle)

                   / nondrying cleansing agent such as Cetaphil

                   / nonlipid lotion

           - minimum bathing

           - avoidance food aggrevating itching

                   / 정확한 검사를 통하여 회피

                   / reintroduction within 2-4yr

# Food Allergen Sensitization 줄이기 위한 방법

    1. breast milk feeding

    2. delaying the introduction of solid food until after 6 mo of life

    3. breast-feeding mother should avoid high risk food

# Local Therapy

    ; *mainstay of management

    1) wet dressing

           ; Burow solution 1:20

                   - antipruritic & anti-inflammatory effect

    2) topical corticosteroid lotion or creams

    3) itching control

           ; *almost impossible to manage during infancy & early childhood

           ; cutting fingernail

           ; *difficut to control with drugs

                   - both sedative & antihistamine activity

             / *diphenhydramine (Benadryl), hydroxyzine (Atatax, Vistaril), promethazine (Phenergan)

                           / *value

                   - aspirin

# infection control

    ; if infection(acute weeping or crusting)

           --> systemic AB

           - EM or cephalexin

                   / prudent choice

    ; local AB

           - *little therapeutic value

           - *exception) Mupirocin(Bactroban)

# after the acute phase subsided

    ; topical steroid cream & ointment of great value

    ; 0.1% topical triamcinolone acetonide ointment often useful

# after improvement

    ; less potent corticosteroid

# potent topical steroid face 금기

    ; *0.5 or 1 % hydrocortisone 적당

# systemic corticosteroids

    ; avoided except severely affected patients

# *Topical Coal Tar Preparations

    ; Estar gel(Westwood) and psoriGel(Owen)

           - effective & more acceptable

# experimental therapy

    ; interferon gamma, cyclosporine, chinese herb

Table 138-3

Prognosis

; resolution occurs within 5yr usually.

Chapter 139. Urticaria-Angioedema(Hives)

Clinical Manifestations

urticaria (or hive)

- characterized by usually well-circumscribed but sometimes

  coalescent. localized, or generalized erythematous raised skin   lesion

  usually resolve within 48hr

  intensely pruritic or itch little

  chronic urticaria - 6 이상지속시

Angioedema (angioneurotic edema)

- deeper layer of skin or submucosa & subcut. or other tissue   involve

- urticaria 구별점

: common target organ : upper resp. tr. GIT

Incidence

female> male

Pathogenesis

(1) interaction of Ag. with mast cell  or basophil-bound IgE Ab.

   : principal noncytotoxic mechanism

  - histamine release

    - vasodilatation, increased vascular permeability, stimulate axon  reflex

    - typical wheal & flare reaction

 - leukotriene release

    - edema of IgE-mediated reaction

(2) complement system activation

   C3a & C5a

- act as anaphylatoxin & trigger histamine release from mast cell  & basophil by direct    action on the cell surf., independent of Ab.

(3) plasma kinin-forming system of the coagulation scheme

  : bradykinin - increase vascular permeability

Etiology

Table 139-1

Differential Diagnosis

allergy skin test is generally not helpful except when specific drug or food allergy are identified

# TMC cause of urticaria : drug & food

# Chronic urticaria 원인은 10%에서만 identify.

#  cholinergic urticaria

    wheal 1-2 mm in diameter surround by erythema

    frequently involve skin of the neck

    cause : exercise

            hot showers

            anxiety

            viral infection . hepatitis, infectious mononucleosis

  전형적인 hives 자발적으로 erythema multiforme  lesion으로 변하면 drug allergy    sign 있다.

# Urticaria pigmentosa : Systemic mastocytosis

# adult에선 urticaria malg. collagen-vascular disorder 관련  

# cold urticaria : mc form caused by physical factor

 - exposure to cold & confined to the exposed part of body

 - 2 forms : priamry acquired form & familial type.

 - systemic ds 관련 : cryoglobulinemia, cryofibrinogenemia,    

                       cold-agglutinin ds, 2ndary syphilis.    

# Hereditary angioedema ;life-threatening form

# Exercise-induced anphylaxis

Treatment

(1) antihistamine

hydroxyzine(atarax) - most effective for control of urticaria,

                     0.5 mg/kg

diphenhydramine - 1.25 mg/kg

(2) epinephrine - 1:1000, 0.01 ml/kg, max 0.3 ml

(3) corticosteroid

- urticaria 조절하기 위해서는 다량이 필요해 부작용 유발 가능

cholinergic & chronic urticaria : hydroxyzine

prophylactic agent for cold urticaria : cyproheptadine (periactin)

Chapter 140. Anaphylaxis

Definition

; acute, potentially life-threatening reactions caused by release of mediators from mast cells & basophils

; *interaction of allergen with specific, cell-bound Ig E

Etiology

; 대부분 drugs, food, hymenoptera venom allergy

Table 140-1

Pathogenesis

# IgE-mediated anaphylactic sensitivity to an Ag.

# Other mechanisms

    ; *direct effect of causative agent on basophils and mast cells

    ; *by activation of alternative complement pathyway with anaphylactoxin

    --> 증거

           : decreased factor V & Vlll - DIC 암시

           : *decreased HMW kininogen, C3 & C4

Clinical Manifestations

; *characterically explosive, particularly when the antigen is injected

; *tingling sensation around mouth or face

    --> feeling of warmth, difficulty in swallowing, tightness in throat or chest

    --> apprehension, weakness, diaphoresis

    --> general prutitis

    --> flushed

    --> urticaria & angioedema

    --> hoarseness, inspiratory stridor, dysphagia, nasal congestion, itching of eyes, sneezing, wheezing

    --> abdominal cramp, diarrhea, contraction of uterus and other organ

    --> loss of consciousness

    --> hypotension, feeble heart sounds, bradycardia

    --> cardioresoiratory arrest

    --> death

; *cause of death

    - *most often acute upper airway obstruction

; *begin within 30min

    --> resolve within a few hours

Treatment

1. epinephrine 1:1000, 0.01 ml/kg (max, 0.3 ml) -BP; 80mmHg유지

2. tourniquet above the site

3, aminophylline, nebulized albuterol; Lower aw obst 효과.

4. volume expander for hypotension. CVP측정이 필요

5. 02

6. antihistamine: diphenhydramine, cimetidine

 

corticosteroid - not useful as emergency

      may be useful in preventing the recurrence of symptom during 12-24hr following        the acute reaction

contrast media 의한 anaphylaxis 소아에서 less common

prophylactic regimen

1. prednisone, 50 mg orally every 6 hr for 3 doses, ending 1 hr   before procedure

2. diphenhydramine, 50 mg, given by im 1 hr before procedure

Chapter 141. Serum Sickness

a characteristic systemic immunologic disorder that follows the administration of foreign antigenic materials

Etiology

1. adverse reaction to the serum proteins of the animal in which antitoxin was prepared

2. drug allergy - major cause, penicillin

3. human gamma globulin

4. hymenoptera stings

Pathogenesis

; *type III hypersensitivity."immune complex disease"

  - these complex activate the complement sequence

  - promote accumulation of neutrophils

  - tissue injury result from liberration of toxic molecules from the  neutrophils

# urticaria

- due to IgE Ab. molecules reacting with horse serum protein

# joint symptom

- due to deposition of Ag.-Ab. complex of the IgG & IgM classes

# Histamine

-facilitates the deposition of immune complexes through increase in vascular permeability

Clinical Manifestations

    ; *typically, begin 7-12 days following injection of foreign material

           - may appear as late s 3wk afterward

fever & malaise, urticaria ; common finding

characteristic cutaneous lesion

- faint erythema with a serpiginous border at the margin of palmar or plantar skin of

  the hands, fingers, feet, & toes

- become pruritic with time

recover in 7-10 days

    ; *carditis & glomerulonephritis - rare

    ; *Guillain-barre syndrome & peripheral neuritis, involving brachial plexus (C5-C6)

           - *serious complication

Laboratory Manifestations

    ; marked thrombocytopenia

    ; ESR

    ; *C3 & C4 around 10th day

Treatment

    ; *aspirin & antihistamine

corticosteroid - severe sx. effective

Prevention

skin test

epinephrine & antihistamine before beginning injection

Chapter 142. Adverse Reactions To Drugs

Definition

any unwanted consequence of administration of the agent during or following a course of therapy

# 2 broad categories : pharmacologic & immunologic mechanisms

# certain generalities apply to adverse drug reactions

(1) any organ system may be involved

(2) children are less often affected than adult

(3) incidence of reactions increase with the numbers of drug given simultaneously

(4) certain diseases predispose to adverse drug reaction, esp. those in which multiple        drug therapy is common.

   diseases that affect organ responsible for absorption. metabolism, or excretion of drug

   also increase the likelihood of adverse  reaction

(5) pharmacokinetic properties of a drug also affect the incidence of adverse reaction

Classlflcatlon

 toxicity - high concentration of drug in the body due to excessive intake, or to     

           abnormalities in absorption, metabolism, or  excretion of drug

# intolerance - excessive pharmacologic responses to average drug dosage

# side effect - undesirable but essentially unavoidable effects of drugs

              and largely reflect the fact that a given drug rarely affects only one                    tissue

        eg. theophylline - CNS stimulation

# secondary effect - those not related to their primary

                     pharmacologic  action

        eg. antibiotic therapy - disturbance of the bacterial flora of  the intestine

# idiosyncracy - sg. & sx. of the reaction are unrelated to the  known pharmacologic

                properties of the agents

      eg. G- 6-PD deficiency primaquine - hemolytic anemia야기

# allergic drug reactions occur on the basis of recognized models of  immune injury

(I) IgE-mediated reaction

(2) cytotoxic reactions resulting from hapten binding to cell

   membrane & subsequent reaction with anti-hapten Ab.

(3) immune complex reaction, activate the complement system

(4) reaction due to autoAb. formation

(5) cell-mediated mechanism

# Penicillin allergy

  minor hapten determinants 의해 발생

- penicilloate, penilloate, penicillenate, oxidative product

# ampicillin rash

   not urticarial, 10%, (urticaria-1%)

   infectious mononucleosis, hyperuricemia 환자의  90%에서 발생

Clinical Manifestations

    ; cutaneous manifestation

           - *common

           - utricaria, exanthematous & eczematoid eruption

    ; renal or pulmonary diseases

           - rarely occur during childhood

  ; phenytoin - interstitial nephritis

    ; drug fever

- a child who has received prolonged antimicrobial therapy has

   persistent fever without other cause  concornitant rash

 Dx. drug D/C 24-48 시간뒤 fever down

 immunologically mediated drug-induced reactions involving liver,  

 disorder of granulocytes & platelet are extremely rare in chiIdren

Risk Factors

# one parent with allergy to antimicrobial drugs

    ; *25% of children risk for allergy rather than 2% in no allergic parents

# Other Risk Factors

    ; dose, route, duration, frequency

           - large dose

           - topical administration

           - nonoral adminstration

           - frequent, intermittent adminstration

Diagnosis

Treatment Of Drug Reactons

antihistamine - diphenhydramine, hydroxyzine

epinephrine

corticosteroid - severe case

Prevention

Capter 143. Insect Allergy

allergic reactions to insects can cause

(1) symptoms of resp. allergy due to inhalation of particulate matter

   of insect origin

(2) local cutaneous reactions to insect bites

(3) anaphylactic reactions to stinging insects

Etitology

Pathogenesis

IgE-mediated sensitivity to antigenic materials found in the insect bodies stinging insect venoms contain at least 9 components that contribute to adverse reaction

 - vasoactive material : histamine, acetylcholine. kinins

   enzyme : phospholipase A & B. hyaluronidase

   apamine,melittin,formic acid

Clinical Manifestations

rhinitis, conjunctivitis, asthma

cutaneous lesion- urticaria(most often) maybe papule,vesicle,  erythema

late sequelae - serum sickness, nephrotic syndrome, vasculitis,

               neuritis, encephalopathy

Diagnosis

Treatmemt

# previous severe or anaphylactic reation to Hymenoptera stings

    ; equipped with EpiPen or EpiPen Jr

    ; wear identification bracelet(Medic-Alert)

# Immunotherapy

    ; children

           - *severe systemic reaction(airway involvement or hypotension) & positive skin test

           - *not indication with only urticarial or local reaction

    ; adolescent & adult

           - positive skin test & non-life-threatening or life-threatening systemic rxn

           - not indication

                   / negative skin tests and RAST

Chapter 144. Ocular Allergies

   less common in children

mechanism - IgE-mediated allergy : ragweed hay fever

             cell-mediated (delayed hypersensitivity) : contact dermatitis

Eyelids

chronic staphylococcal infection : major cause of chronic eczema of eyelid

Allergic Conjunctivitis

watery secretion

purulunt secretion이라도 eosinophil predominant infectious 감별

# vernal conjunctivitis

  male : female = 3 : 1

  warm climate & during the spring & summer

  2 forms

         *palpebral form - cobblestone appearance

         *limbal form - Trantas dots : represent accumulation of  eosinophil              IgE-mediated sensitivity

  immunotherapy - of little value

Chapter 145. Adverse Reactions To Foods

; *mostly adverse reactions to food don't have immunologic basis

; *immunologic test & therapy are unwarranted

Etiology

allergy

enzyme deficiency

nonimmunologic reaction to tyramine, nitrite & monosodium  glutamate  macromolecules may pass through the epithelium of the GIT &   gain access to systemic circulation

   - secretary Ig.A limit absorption of intact macromolecules

      pt with IgA deficiency, higher level of Ab. to cow milk  

      protein & of immune complex containing milk

#. a variety of reactions have been reported to follow ingestion of cow milk by infant &

  children

1. IgE mechanism

2. Ab. to milk protein, α-lactalbumin, β-lactoglobulin. & casein

3. no immunologic mechanism

# cow milk ingestion

   during the 1st yr of life

    - vomiting & watery,blood-streaked,mucoid diarrhea may follow young infant fed large vol.of whole pasteurized milk

    -enteropathy c loss . recurrent reontgenograohic pul.infiltrate  

 older infant

    -occult fecal blood loss,recurrent roentgenograpnic pul.infiltrate & multiple                       precipitating Ab.to cow milk protein

Diagnosis

-elimination from the diet for period of 7-10 days of a food causing 

 difficulty should generally result in in improvement in sx.

-reintroduction of the food, within 7 days at most food challenge   test

- skin test - anaphylactic food allergy 위험

- RAST

  excellent for codfish, egg white, nut, peanut, peas

  poor in cereal, soybean & white beans

Treatment

foods most likely to become tolerated uith the passage with time

- cow milk,eggs & soys

hypersensitivity to peanut,nut,fish persists for long period