Allergy 2011

Four Types of Hypersensitivity Reaction

Type I

Type II

Type III

Type IV

Type I Hypersensitivityallergen

Fc receptor

mast cell degranulation mediator release

Type II HypersensitivityKtarget cell

cytotoxic actionantibodycomplement target cell

complementmediated lysis

Type III Hypersensitivityimmune-complex deposition

complement

tissue basement membrane

Blood Vessel

Type IV Hypersensitivityantigens T inflammatory mediators

lymphokines

activated macrophage

ALLERGIC PROCESS

Pathophysiology of Type I Allergic Reaction Sensitization Phase:Initial antigen exposure

InternalizationAntigen-presenting cell (macrophage, dendritic cell, Langerhans cell) IL-3 IL-4 IL-5 IL-13 GM-CSF Circulating TH2 lymphocyte Systemic allergen-specific IgE

B lymphocyte

Plasma cell

IgE binds to basophils and Mast cells

Pathophysiology of Type I Allergic Reaction Re-exposure Phase:Initial antigen exposure

InternalizationAntigen-presenting cell Antigen re-exposure IL-3 IL-4 IL-5 IL-13 GM-CSF Circulating TH2 lymphocyte Systemic allergen-specific IgE Degranulation and release of mediators and synthesis of new mediators

B lymphocyte

Plasma cell

IgE binds to basophils mast cells

Allergen-antibody crosslinking

Early Phase Allergic ResponseAn t ige n Na s al e pit h el ium

Sne eze /I t chA nt ig en + CNS/Peripheral nerves

Ma st ce ll

Hi sta mine LTs PGs Tr y pt a se + Ex udat io n Vas od ilat io n

+

+

R hin or rh ea Muc os a l e de ma

CNS = Central nervous system.

Late Phase Allergic ResponseAntigen Nasal epithelium Antigen Mast cell

IL-5 Eotaxins RANTES

+

IL-4 IL-13 Cellular infiltration Eosinophils: MBP ECP , Basophils: Cytokines Chemokines T lymphocytes Macrophages

+Bone marrow

Adhesion molecules (ICAM-1) Basophil Basophils s

+

+RANTES Endothelium

+

Eosinophils

Chronic nasal obstruction

RANTES = Regulated on activation, normal T cell expressed and secreted; ICAM = Intercellular adhesion molecule; MBP = Major basic protein; ECP = Eosinophil cationic protein.

Broad Allergic Cascade MediatorsEarly Phase

Late Phase

ALLERGIC PROCESSMast-cell activation & physiological effects of mast-cell derived mediators

ALLERGIC DISEASESHIYASMIN M. LIM, M.D.

APPROACH TO DIAGNOSISI.

ALLERGIC HISTORY PHYSICAL EXAMINATION

II.

III.I. II.

LABORATORY PROCEDURESCBC TOTAL EOSINOPHILIC COUNT SMEAR FOR EOSINOPHILS TOTAL SERUM IgE SKIN TESTS IN-VITRO TEST

III.IV. V. VI.

Skin Testing

Skin Testing

PROVOCATIVE TESTS VIII. X-RAY, CT Scan, MRI IX. PULMONARY FUNCTION TEST X. PASSIVE CUTANEOUS TESTING XI. MISCELLANEOUS TESTVII.

Peakflow Measurement

BASIC PRINCIPLES OF THERAPY FOR ALLERGIC DISEASE GENERAL PRINCIPLES: AVOIDANCE

OF ALLERGENS & IRRITANTS JUDICIOUS USE OF PHARMACOLOGIC THERAPY ADMINISTRATION OF IMMUNOTHERAPY

I. AVOIDANCE OF ALLERGENS AND IRRITANTS Standard environmental

control

Mechanical devices Specific

control measures

II.PHARMACOLOGIC MANAGEMNT OF ALLERGIC DISEASE Antihistamine Adrenergic

drugs methylxanthines Anticholinergic Cromolyn and Nedocromil Corticosteroid Leukotriene antagonists Anti-IgE

III.IMMUNOTHERAPY

ALLERGIC RHINITIS

ALLERGIC RHINITIS

a symptomatic disorder of the nose induced by an IgE-mediated inflammation after allergen exposure of the membranes of the nose

Pathophysiology of Type I Allergic Reaction Sensitization Phase:Initial antigen exposure

InternalizationAntigen-presenting cell (macrophage, dendritic cell, Langerhans cell) IL-3 IL-4 IL-5 IL-13 GM-CSF Circulating TH2 lymphocyte Systemic allergen-specific IgE

B lymphocyte

Plasma cell

IgE binds to basophils and Mast cells

Pathophysiology of Type I Allergic Reaction Re-exposure Phase:Initial antigen exposure

InternalizationAntigen-presenting cell Antigen re-exposure IL-3 IL-4 IL-5 IL-13 GM-CSF Circulating TH2 lymphocyte Systemic allergen-specific IgE Degranulation and release of mediators and synthesis of new mediators

B lymphocyte

Plasma cell

IgE binds to basophils mast cells

Allergen-antibody crosslinking

ALLERGIC RHINITISTypical Symptoms: sneezing clear rhinorrhea nasal itching nasal congestion reversible, spontaneously or with treatment

ALLERGIC RHINITISSigns / Symptoms: mouth breathing or snoring sleep disturbance abnormalities of facial development, dental malocclusion & allergic facies

ALLERGIC RHINITISSigns / Symptoms: frequent throat clearing chronic postnasal drip chronic, nonproductive cough

ALLERGIC RHINITIS

Facial Grimace

ALLERGIC RHINITIS

Allergic Hand Salute

ALLERGIC RHINITISSigns / Symptoms: red,itchy eyes itchy throat, ears and palate swollen nasal turbinates

ALLERGIC RHINITIS

Allergic Shiners

ALLERGIC RHINITISSigns / Symptoms: eustachian tube dysfunction ear fullness sinus headache malaise, weakness and daytime fatigue

Skin Testing confirms sensitivity to allergens

After 15 minutes:

Classification of Allergic RhinitisIntermittent symptoms < 4 days per week or 4 days / week and >4 weeksModerate-Severeone or more items

abnormal sleep impairment of daily activities sport, leisure problems caused at work or school troublesome symptoms

Treatment of allergic rhinitis (stepwise approach)Moderate Mild severe persistent persistent

Moderate severe intermittent Mild intermittent Intra-nasal steroid Antileukotrienes Oral or local non-sedative antihistamine Intra-nasal decongestant (< 10 days) or oral deco Allergen and irritant avoidance Immunotherapy

Frequency and Severity of Symptoms

Algorithm for Allergic Rhinitis Diagnosis and Management (2007)Diagnosis of allergic rhinitis(history + skin prick tests or serum specific IgE)

Allergen avoidance Intermittent symptoms mild Not in preferred order Oral H1-antihistamine Intranasal H1-antihistamine And/or decongestant Antileukotrienes * moderate- severe Not in preferred order Oral H1-antihistamine Intranasal H1-antihistamine And/or decongestant Antileukotrienes * (chromone) Intranasal CS (300-400 ug daily) (100-200 ug daily) Persistent symptoms

Check for asthma especially in patients with moderate-severe and/or persistent rhinitis

mild

moderate severe In preferred order Intranasal CS (300-400 ug daily) H1-antihistamine or Antileukotrienes * review the patient after 2-4 weeks

improved step-down and continue treatment for 1 month

failure review diagnosis review compliance query infections or other causes Blockage add decongestant or oral CS short term failure Surgical referral

in persistent rhinitis review the patient after 2-4 weeks If failure: step-up If improved; continue for 1 month

rhinorrhea increase intranasal CS add ipatropium dose Itch/sneeze add H1 blocker

* In particular, in patients with asthma

TREATMENT OF ALLERGIC RHINITIS:

ALLERGEN IMMUNOTHERAPY

ANAPHYLAXISHIYASMIN M. LIM, M.D.

DefinitionAnaphylaxis is a severe life-threatening generalized or systemic hypersensitivity reaction.o

It is commonly, but not always, mediated by an allergic mechanism, usually by IgE. Allergic (immunologic) non-IgE-mediated anaphylaxis also occurs.

o

o

Non-allergic anaphylactic reactions, formerly called anaphylactoid or pseudo-allergic reactions, may also occur.

Johansson SGO et al JACI 2004,113:832-6

Revised nomenclature for anaphylaxisAnaphylaxis

Allergic anaphylaxis

Non-allergic anaphylaxis

IgE- mediated anaphylaxis

Immunologic, non-IgEmediated anaphylaxis

Johansson SGO et al JACI 2004,113:832-6

Epidemiologyo

Prevalence of anaphylaxis may be as high is 2% Recent studies in 2009 show that the prevalence is rising, esp in younger age grp. There is an increase in fatalities and increase in hospitalizations

o

o

Lieberman, 2010 Practice Parameter Update, August 2010 Lieberman, JACI, 2006

Mechanisms and Triggers

Hidden allergens Mastocytosis/clonal mast cell disorder

Simons, JACI, February 2010

Pathogenesis

Simons, JACI, October 2009

Simons, JACI, July 2007

Simons, JACI, July 2007

Symptoms of anaphylaxisOral:Pruritus of lips, tongue, and palate Edema of lips and tongue Metallic taste in mouth

Respiratory Nose:Pruritus Congestion Rhinorrhea Sneezing

Cutaneous:Flushing Pruritus Urticaria Angioedema Morbilliform rash Pilor erecti (atopic dermatitis)

Respiratory Laryngeal:Pruritus Tightness in the throat Dysphagia Dysphonia and hoarseness / stridor Dry staccato cough Sensation of itching in the external

auditory canals

Gastrointestinal:Nausea Abdominal pain (colicky) Vomiting (large amount of stringy mucus) Diarrhea

Respiratory Lungs:Shortness of breath Dyspnea Chest tightness Cough Wheezing

Others:Periorbital pruritus, erythema, and edema Conjunctival erythema and tearing Lower back pain and uterine contractions in women Aura of impending doom Seizures

Cardiovascular:Feeling of faintness Syncope Chest pain Dysrhythmia Hypotension with compensatory tachycardia

Patterns of anaphylaxiso

Acute explosive onset within seconds to minutes of exposure to triggering event Biphasic followed by a reaction 3-8 hours after initial reaction (5-20%) Protracted lasts 3-21 days from onset of reaction

o

o

Lieberman P. Ann Allergy Asthma Immunol 2005;95:217-26 Leung et al, Pediatric Allergy: Principles and Practice 2003

Anaphylaxis is highly likely when any one of the following three criteria are fulfilled:

1. Acute onset of an illness (minutes to hours) with involvement of the skin and/or mucosal tissue; and at least one of the following: a. Respiratory compromise b. Reduced blood pressure

Sampson et al, Second symposium of the definition and management of anaphylaxis: Summary report; JACI 2006;117:391-7


2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient: a. Involvement of the skin/mucosal tissue (hives, itch/flush, angioedema) b. Respiratory compromise c. Reduced BP or associated symptoms d. Persistent GI symptomsSampson et al, Second symposium of the definition and management of anaphylaxis: Summary report; JACI 2006;117:391-7


3.

Reduced BP following exposure to a known allergen for that patient. a. Infants and children: low systolic BP (age specific) or >30% drop in systolic BP. b. Adults: systolic BP 30% drop from the individuals baseline.

Sampson et al, Second symposium of the definition and management of anaphylaxis: Summary report; JACI 2006;117:391-7

Simons et al ., JACI, July 2007

Simons, et al ., JACI, July 2007 ak ., JACI, July 2010 Simonsm et and February 2007

Therapeutic Principles: Immediateo o o o

RAPID recognition ABCs of resuscitation Epinephrine

O2 100% and secure and maintain airway

Physician-supervised management of anaphylaxisII. Secondary measures: a) place patient in recumbent position and elevate his/her legs

b) maintain airway (endotracheal tube or cricothyrotomy)c) oxygen, 6 - 8 liters/minute d) normal saline IV; volume expanders (colloid solution) for

severe hypotension

Kemp SF and Lockey RF. J Allergy Clin Immunol 2002;110:341-8

Physician-supervised management of anaphylaxisIII. Other measures:

a)

epinephrine 1:1000, dose (0.1- 0.2 mg) into reaction sitediphenhydramine, 50 mg IV or orally (1.25 mg/kg, up to 50 mg dose for children); maximum daily dose: adults 400 mg; children

200 mgb) dilute in 5% D/W, total 20 ml, inject slowly IV, over 5 minutes

ranitidine, 50 mg in adults and 12.5 - 50 mg (1 mg/kg) in children,

(cimetidine 4 mg/kg OK for adults, dose not established forchildren)Kemp SF and Lockey RF. J Allergy Clin Immunol 2002;110:341-8

Physician-supervised management of anaphylaxiso

for bronchospasm- nebulized salbutamol 2.5 - 5 mg in 3 ml normal saline for refractory hypotension

o

- dopamine, 400 mg in 500 ml NSS IV 2 - 20 g/kg/min- glucagon, 1- 5 mg (20 - 30 g/kg, max 1 mg in children), IV over 5 minutes followed with continuous IV infusion 5-15

ug/min- methylprednisolone, 1- 2 mg/kg per 24 hrKemp SF and Lockey RF. J Allergy Clin Immunol 2002;110:341-8

Complicationso

Deatho

Laryngeal edema, respiratory failure, shock, cardiac arrhythmia

o

In fatal anaphylaxis, death occurs w/in 1 hour of onset of symptoms

Long Term Managementoo

Risk assessmentRisk reduction strategies (personalized) Anaphylaxis education

o

Prevention of Anaphylaxis in community setting

o

o

o

o

Anaphylaxis is a severe life threatening reaction that can affect all age groups The severity of previous reactions does not predict the severity of subsequent reactions Intramuscular epinephrine is the first line treatment for anaphylaxis - Intravenous epinephrine reserved for unresponsive anaphylaxis or circulatory collapse Early use of epinephrine in anaphylaxis is associated with improved outcomes

Any patient with a systemic allergic reaction should be

considered for an epinephrine auto-injector, depending on risk of further reactions Injectable Epinephrine is the first line of treatment There is a clear need to improve education of both

patient and physician on the use of and indications for epinephrine auto-injectors Hallmarks of management: education and prevention

FOOD ALLERGY

ADVERSE REACTION TO FOOD ( European Classification )

Non toxic

Toxic

Food allergy

Non- IgE

Food Intolerance Enzymatic Pharmacologic IgE Undefined

FOOD ALLERGENS

CHILDREN:

MILK, EGGS, PEANUTS SOY,WHEAT FISH, SHELLFISH PEANUTS, NUTS

ADOLESCENTS: AND ADULT

Prevalence of food allergy-up to 8% of children12 yrs ) increased scaling decreased excoriation

flexural areas dorsum of hand

Hanifin and Rajka CriteriaMAJOR CRITERIA:

pruritus chronic or relapsing course personal or family history of atopy typical distribution of dermatitis facial and extensor surfaces in children2 or adults

PRURITUS

quintessential feature mild to extremely intense innate perception of touch as itch itch when scratched erupts

Hanifin and Rajka CriteriaMINOR CRITERIA: early age of onset xerosis ( dryness ) facial pallor or erythema infraorbital darkening white dermographism

Hanifin and Rajka CriteriaMINOR CRITERIA: hypopigmented patches Dennie-Morgan infraorbital fold Ichthyosis/ palmar hyperlinearity/ keratosis pilaris Non-specific hand and foot dermatitis

Hanifin and Rajka CriteriaMINOR CRITERIA: nipple eczema cheilitis itch when sweating intolerance to wool /irritants course influenced by environmental or emotional factors

Hanifin and Rajka CriteriaMINOR CRITERIA: elevated serum IgE immediate (Type 1) skin test reactivity food allergy / intolerance susceptibility to cutaneous infections

NON-IMMUNOLOGIC PRO-INFLAMMATORY MECHANISMS IN AD Lower itch threshold Cutaneous hyperreactivity Defective skin barrierDecreased skin ceramide levels

Decreased water bindingImokawa G et al J Invest Dermatol 1991

Defective metabolism of essential fatty acids (Delta-6-desaturase)Manker et al PGLT Med 1982

SPECTRUM OF ITCH TRIGGERS IN AD

Xerosis Irritants Food/Aeroallergens Microbes Others (Psychological stresses, climate, hormones)

APPROACH TO THE MANAGEMENT OF ATOPIC DERMATITIS

Cutaneous hydration Identification/elimination of triggers

Pharmacotherapy Patient education/counseling

PHARMACOTHERAPY Anti-inflammatory drugs Corticosteroids Calcineurin Inhibitors

Antipruritic Agents Antihistamines Alternative Therapies

ALTERNATIVE THERAPIES Interferon y Intravenous Ig

Leukotriene Antagonists Phosphadiesterase inhibitors Tar Preparations/ PUVA Chemotherapy (methotrexate, cyclosporine, azathioprine) Allergen immunotherapy Chinese herbal medicine Hospitalization

DRUG ALLERGY

Adverse Drug Reactions (ADR) Undesired

or unintended responses that occur at doses of an appropriate drug given for the therapeutic, diagnostic, or prophylactic benefit of the patient.

WHO Adverse Reactions Terminology Augmented / predictable reactions Bizarre / unpredictable reactions Continuous use Delayed effect End of use (withdrawal)

Failure of treatment

Bizarre or Unpredictable Reactions Intolerance Drug

allergies Pseudoallergic / anaphylactoid reactions Idiosyncratic reactions

Pseudoallergy or Anaphylactoid ReactionsC3a, C5a

Mast cell

Arachidonic acid

Opiates Vancomycin Curare

RCM

Lipoxygenase

Cyclooxygenase

r

IVIG

h

Leukotrienes

Prostaglandins

r

Aspirin NSAIDs

00

Drug Allergy: Definition Immunologically

mediated reactions to drugs or its metabolites

Immunopathology of Drug AllergyGell & Coombs Classification Immunoreactants Clinical presentation

Type IRBC

AnaphylaxisIgG or IgM

Type I I

Immune cytopenias Serum sicknessContact dermatitis

Type III Type I VTH CD4

IgG

Modified Gell & Coombs Type IV ReactionTypesCells & Mediators involvedIFN-g TNF APC TH1 IL-5 IL-4, 13 TH2Granzymes Perforins

Associated Reactions ExamplesAb production ] Contact Type II & III rxn dermatitis CD8 activation]Type IVc rxn

IV a

Monocyte

IV b

IgE production ] Type I rxn

Maculopapu-lar exanthem

IV cIV d

CD4 CD8 CTL IL-8 GM-CSF

Keratinocytes

Commonly associated Bullous skin lesions with other type IV reactions Acute generalized exanthematous pustulosis

Modified from Pichler WJ. Drug Hypersensitivity. 2007

DRUG HYPERSENSITIVITY DRUGS Beta

FREQUENTLY IMPLICATED:

lactam antibiotics Aspirin and other NSAIDs Sulfonamides Anti-TB Anti-convulsants General anesthesia Radio contrast media Allopurinol others

ADRs in Out-Patient Setting at UP-PGHOthers 22%Anticonvulsants 6% NSAIDS 10%

Antibiotics 35% AntiKochs 27%

Risk factors for drug hypersensitivity Dose & duration of treatment Frequency of treatment Polymerization Protein reactivity Route of administration

Drug factors Prior reaction Female sex Atopy MDAS Persistence of drug specific IR Genetic predisposition

Patient factors

Disease states

EBV & AIDS Concomittant drugs

Chronic/recurrent illnesses137

Celik, G et al. Drug Allergy in Middletons Allergy: Principles & Practice, 7th ed 2009. P 1205-1226

CHARACTERISTICS of ALLERGIC DRUG REACTION Occurs Usually

in small number of patients

requires previous exposure to the same or chemically related drugs rapidly after exposure

Develops Produce

clinical syndromes associated with allergic- immunologic reactions

Clinical classification of allergic reactions to drugsGeneralized or multisystem involvementImmediate generalized reactions Anaphylaxis (IgE-mediated reactions) Anaphylactoid reactions (IgE-independent) Serum sickness Drug fever Drug-induced autoimmunity Reaction simulating systemic lupus Other reactions Hypersensitivity vasculitis

Clinical classification of allergic reactions to drugsReaction predominantly organ specificDermatologic manifestation Pulmonary manifestation Hematologic manifestation Hepatic manifestations Renal manifestations Lymphoid system manifestations Cardiac manifestations Neurologic manifestations

Evaluation of patients with suspected drug hypersensitivityDetailed history basis for diagnosis in most cases Consider the possibility Complete history of all drugs taken and any prior reactions Compatible clinical manifestations Temporal eligibility In vivo testing clinically indicated in some cases Cutaneous test for IgE-mediated reaction Patch tests Incremental provocative test dosing

Evaluation of patients with suspected drug hypersensitivityIn vitro testing rarely helpful clinically

Drug-specific IgE antibodies (UNICAP) Drug-specific IgG and IgM antibodies Lymphocyte blast transformation Others: mediator release, complement activation, immune complex detection

Withdrawal of the suspected drug-presumptive evidence if symptoms clear

Eliminate any drug not clearly indicated Use alternate agents if possible

Treatment of Drug Hypersensitivity1.

2.3. 4.

5.

Discontinue the responsible drug Give symptomatic treatment for ongoing drug reaction In indicated, substitute a non-cross reacting drug. If there is no adequate substitute and the skin test is negative, do TEST DOSING If the skin test if positive, do DESENSITIZATION Previous severe IgE mediated (anaphylaxis) reaction, forego skin test, DESENSITIZE.

Drug Hypersensitivity Prevention Ascertain

host risks Avoid cross-reactive drugs Use of predictive skin tests Prudent use of drugs Preferential use of oral drugs

ASTHMA

ASTHMA Chronic

inflammatory disorder of the airways in which many cells and cellular elements play a role Associated

with AIRWAY HYPERRESPONSIVENESS

Wheezing, breathlessness, chest tightness and cough

Associated

with AIRFLOW OBSTRUCTION

FACTORS INFLUENCING THE DEVELOPMENT AND EXPRESSION OF ASTHMA HOST

FACTORS

Genetic Obesity Sex

FACTORS INFLUENCING THE DEVELOPMENT AND EXPRESSION OF ASTHMA

ENVIRONMENTAL FACTORS

Allergens INDOOR: domestic mites, furred animals, cockroach, fungi Infections Occupational sensitizers Tobacco smoke Passive smoking Active smoking Outdoor/ indoor pollution Diet

PATHOPHYSIOLOGY of ASTHMA Airway

Narrowing

Factors

contributing to airway narrowing: Airway

smooth muscle Airway edema Airway thickening Mucus hypersecretion

AIRWAY HYPERRESPONSIVENESS Mechanism Excessive

contraction of airway smooth

muscles Uncoupling of airway contraction Thickening of the airway walls Sensory nerve sensitization by inflammation

MECHANISM OF ASTHMA

Inflammatory cells in Asthma Mast

cells Eosinophils T-lymphocytes Dendritic cells Macrophages Neutrophils

MECHANISM OF ASTHMA

Key Mediators Chemokines Cysteinyl

leukotrienes Cystokines Histamine Nitric oxide Prostaglandin

3 CATEGORIES of WHEEZING

TRANSIENT EARLY WHEEZING

Associated with prematurity and parental smoking

PERSISTENT EARLY ONSET WHEEZING

Associated with viral respiratory infection; (-) personal, family history of atopy

LATE ONSET WHEEZING/ ASTHMA

Persistent throughout childhood and into adult life (+) history of atopy Airway pathology characteristic of asthma

LEVELS of ASTHMA CONTROLCHARACTERISTIC CONTROLLEDDAYTIME SYMPTOMS LIMITATION OF ACTIVITIES NOCTURNAL SYMPTOMS AWAKENINGNEED FOR RELIEVER/ RESCUE TREATMENT

PARTLY CONTROLLED > 2x per week ANY

UNCON TROLLED

NONE (2x or less/ week) NONE

NONE NONE (2X OR LESS/ WEEK NORMAL NONE

ANY > 2X PER WEEK < 80% PREDICTED/ PERSONAL BEST ONE/ MORE PER YEAR

3 or more features of partly controlled

LUNG FUNCTION EXACERBATIONS

Assessment of Severity of Asthma ExacerbationsMILDBreathless when Walking Can lie down

MODERATE

SEVERE

RESP. ARREST IMMINENT

Talking Infants softer shorter cry Prefers sitting Phrases Usually agitated Increased

At rest Infants- stops feeding Hunched forward Words Usually agitated Often > 30/min Drowsy/ confused or comatose Bradypnea

Talks in Alertness Resp. rate

Sentences May be agitated Increased

Guides to rates of breathing associated with respiratory distress in awake children AGE NORMAL RATE >2 months < 60/min 2-12 months < 50/min 1-5 years < 40/min 6-8 years < 30/minPhilippine Consensus for the Management of Childhood Asthma 2002

Assessment of Severity of Asthma ExacerbationsClinical features:

MILDAccessory muscles and suprasternal retractions

MODERATE

SEVERE

RESP. ARREST IMMINENTPresent thoracoabdominal movement Absence of wheeze with decreased to absent breath sounds Bradycardia

None

Present

Present

Wheeze

Audible with stethoscope < 100

Audible with stethoscope 100-120

Audible without stethoscope > 120

Pulse/min

Guides to limits of normal pulse rate in children: Infants 2-12 months normal rate < 160/min Preschool 1-2 years < 120/min School age 2-8 years < 110/min

Pulsus Paradoxus

Absent < 10 mm Hg

May be present 10-20 mm Hg

Often present 20-40 mm Hg

Absence suggests respiratory muscle fatigue

Philippine Consensus for the Management of Childhood Asthma 2002

Assessment of Severity of Asthma ExacerbationsObjective Measures:

MILDPEF % predicted or % personal best paO2 (on air)

MODERATE

SEVERE

RESP. ARREST IMMINENT

> 80%Normal Test not usually necessary < 45 mm Hg

60-79%> 60 mm Hg

< 60%< 60 mm Hg Possible cyanosis

And/ or Pa CO2

< 45 mm Hg

> 45 mm Hg Possible repiratory failure

SAO2% (on air)

> 95%

90-94%

< 90%

Hypercapnea (hypoventilation) develops more readily in young children than in adults and adolescentsPhilippine Consensus for the Management of Childhood Asthma 2002

DIAGNOSIS of ASTHMA CLINICAL:

Based on medical history and physical exam

DIAGNOSIS of ASTHMA

TESTS for DIAGNOSIS and MONITORING

I. Measurement of Lung Function 1. spirometry 2. peak expiratory flow II. Measurement of Allergic Status 1. allergic skin prick testIII. Measurement of Airway hyperresponsiveness 1. airway response to metacholine, histamine, mannitol and exercise challenge

NON-INVASIVE MARKERS of AIRWAY INFLAMMATION Examining

spontaneously produced or hypertonic saline-induced sputum for eosinophil or neutrophil of exhaled nitric oxide and carbon monoxide

Level

ASTHMA MEDICATIONS

CONTROLLER

Inhaled glucocorticosteroid Leucotriene modifiers Long acting inhaled beta 2 agonist Theophylline Cromons Long acting oral beta 2 agonist Anti IgE Systemic glucocorticosteroid Oral anti allergic compounds Others: methotrexate, cyclosporin and gold Allergen specific immunotherapy

ASTHMA MEDICATIONS RELIEVER Rapid

acting inhaled beta 2 agonist Systemic glucocorticosteroid Anticholinergics Theophylline Short acting oral beta 2 agonist Complementary and alternative medications

IMMUNOLOGY MODULE

Hiyasmin M. Lim, MD2006 MWS

Immune ResponseComplex sequence of events triggered by the introduction of a stimulus and usually culminates in the elimination of the provoking agent

2006 MWS

Functions of the Immune SystemDEFENSE

Resistance to infection

HOMEOSTASIS

Removal of worn out selfPerception and destruction of altered or neoplastic cells

SURVEILLANCE

2006 MWS

Four Major Host Defense Mechanisms

Antibody-mediated (B cell) Immunity Cell-mediated (T cell) Immunity Phagocytic Cells Complement System

2006 MWS

Innate Immune Response

NONSPECIFIC

SOLUBLE Anti-microbial enzymes - Lyzozyme Binding Protein - mannose binding protein Complement Acute Phase Reactant - ESR, CRP Vascular & endothelial repair - adhesion molecules CELLULAR Phagocytes Macrophage, monocyte, neutrophil NK Cells ANATOMIC BARRIER Skin, mucus membrane, cilia

CHARACTERISTICS Initial

encounter with pathogenNo

prior exposure needed

Resistance

not improved by repeated infecton

2006 MWS

Adaptive Immune ResponseSPECIFICSOLUBLE Antibodies (Humoral immunity)CELLULAR T-lymphocytes (Cell-mediated immunity) CHARACTERISTICSSubsequent

encounters with pathogen neededNeed

previous exposure and recognition (Self and Non-Self)Resistance

improved by repeated infection

2006 MWS

ANTIGENIC STIMULUSIMMUNE RESPONSE NON-SPECIFICPhagocytosis Inflammation

TOLERANCE

SPECIFIC

HUMORAL2006 MWS

CELL-MEDIATED

IMMUNOPATHOLOGY AUTOIMMUNITY

Failure of appropriate recognition HYPERSENSITIVITY

Overactive immune response IMMUNODEFICIENCY

Failure to produce an adequate immune response

2006 MWS

DefinitionImmunodeficiency is the result of a diverse group of abnormalities of the immune system resulting primarily in an increased incidence of infection

2006 MWS

General Considerations 58% of cases diagnosed in children less than 15 years of age 83% of these are males X-linked recessive, autosomal recessive, autosomal dominant and sporadic inheritance patterns are observed

2006 MWS

10 Warning Signs of Primary ImmunodeficiencyThe Jeffrey Modell Foundation

Eight or more new ear infections within 1 year

Two or more months on antibiotics with little effect

Two or more serious sinus infections within 1 year

Two or more pneumonias within 1 year

2006 MWS


Failure of an infant to gain weight or grow normally2006 MWS

Recurrent, deep skin or organ abscesses

Persistent thrush in mouth, or elsewhere on skin, after age 1


Need for intravenous antibiotics to clear infections2006 MWS

Two or more deep-seated infections

A family history of Primary Immunodeficenc y

Primary Immune Deficiency Congenital and hereditary Caused by heritable defects in specific genes, embryologic abnormality, enzymatic defect, or unknown cause Infrequent

2006 MWS

Primary Immune Deficiency Overall Incidence: 1: 10,000Phagocytic 18%Complement 2%

FrequencyItaly 1:77,000 Japan 1:200,000 Switzerland 1:54,000 Sweden 1:55,000

Cellular10%

Combined 20%

Antibody 50%

AAAAI 20002006 MWS

The Spectrum of Infection Associated with Different Forms of Immune Deficiency DiseaseImmune Deficiency DiseaseB cell (Antibody) Deficiency T cell/Combined Deficiency Phagocyte Deficiency Complement Deficiency2006 MWS

Bacterial

Type of Infection Viral Fungal

Protozoal

+++ +++ +++ +++

+ +++ -

+++ ++

+ +++ -

Clinical PresentationB cell Immune Deficiency Disorders age > 6 months recurrent sinopulmonary infections diarrhea and malabsorption bacterial sepsis rare

2006 MWS

Serum Ig in Newborns

2006 MWS

DiagnosisTests of B-lymphocyte Function Initial Quantitative Ig Isohemagglutinins Protein electrophoresis Antibody responses to immunization Advanced IgG subclass quantitation B-lymphocyte quantitation (CD19 or CD20) Antibody responses to pneumococcal polysaccharides

2006 MWS

Clinical PresentationT cell / Combined Immune Deficiency Disorders presentation in first 6 months failure to thrive recurrent/chronic diarrhea recurrent candidiasis other opportunistic infections

2006 MWS

DiagnosisTests of T-lymphocyte FunctionInitial Total lymphocyte count( Lymphopenia < 1500 cells )

AdvancedT-lymphocyte quantitation Total T-cells (CD3) T-helper cells (CD4) T-suppressor/cytotoxic cells (CD8) Proliferative responses to mitogens, antigens, allogeneic cells

Delayed-type hypersensitivity skin tests( PPD, Candidia, Tetanus, Mumps, Trichophyton

Chest x-ray (infants)2006 MWS

Clinical PresentationPhagocytic Disorders recurrent skin infections mucosal infections & periodontal disease sepsis susceptibility to catalase-positive bacteria delayed umbilical cord separation (in Leukocyte Adhesion Deficiency)

2006 MWS

DiagnosisTests of Phagocytic FunctionInitial Nitroblue Tetrazolium Reduction Test (NBT) Rebuck Skin Window WBC count / morphology

AdvancedPhagocytic assay Chemotaxis assay Bactericidal assay Neutrophil oxidative burst

2006 MWS

Clinical PresentationComplement Component Deficiency associated with recurrent pyogenic infections and connective tissue diseases (esp. C2 and C4) deficiency of components C5 to C8 associated with recurrent Neisseria species infection deficiency of C1 esterase inhibitor associated with hereditary angioedema

2006 MWS

Secondary Immune Deficiency acquired on a transient or permanent basis more common cause of immune deficiency onset at any age result when there is interference of immune function as a result of other illness, injury, or treatment

2006 MWS

Secondary Immune Deficiency Malnutrition HIV Infection Iatrogenic Immunosuppression cancer therapy organ transplantation long-term steroid administration post-splenectomy

2006 MWS

Some Non-immunologic Causes of Recurrent Infections Allergy Anatomic Abnormalities: very enlarged tonsils or adenoids, tracheoesophageal fistula Foreign Body Aspiration Cystic Fibrosis, Alpha-1 Antitrypsin Deficiency, Immotile Cilia

2006 MWS

Some Non-immunologic Causes of Recurrent Infections Bronchopulmonary Dysplasia, Bronchiectasis Aspiration: gastroesophageal reflux, neurologic abnormality Recurrent Exposure: infected water supply, infectious contact

2006 MWS

High Index of Suspicion: 10 Warning SignsDetailed Hx & PE Infections confined to a single organ system

YES

NO

Otherwise good health

Generally poor health

LOCALIZEDConsider: a. Anatomic / structural abnormality b. Chronic irritation / inflammation on site (e.g. allergic diseases) Work-up geared towards area involved Treat as indicated

SYSTEMICIdentify presence of concurrent conditions which predispose to immune deficiency Routine work-up: CBC, albumin, creatinine, LFT, ANA, other chems., radiographies, etc. PRESENT SECONDARY 1. Treat underlying disease 2. Find out specific part of immune system affected

NOT PRESENT PRIMARY Identify specific defect

2006 MWS

CHART NO. 2 Identify specific defect History Identify pathogens (current & past) bacterial / fungal cultures, viral titers, etc. Recurrent bacterial / pyogenic infections Staphylococcus; skin abscesses; Serratia; Aspergillus Suspect Phagocytic defect NBT test Rebuck skin window Chemotaxis Bacterial assay Neisserial; Pneumococci; H. flu, etc. Suspect Complement defect CH50 C3 C4 assay Recurrent fungal / viral / protozoal / mycobacterial infections HIV screening (ELISA) Negative Positive

Probable AIDSSuspect non-AIDS T cell defect CMI skin test CD4 / CD8 ratio Lymphocyte blastogenic assay T cell enumeration

Other bacterial pathogens, esp. encapsulated e.g. Hemophilus, Streptococcus, Pneumococcus, gram (-)ve, etc. Suspect antibody (B cell) defect Quantitative Ig assay Specific ab titers Isohemagglutinins B MWS 2006 cell enumeration

Suspect Combined T and B cell defect Combination of tests Presence of other assoc. syndrome traits e.g. short-limbed dwarfism, thrombocytopenia.etc.

Summary Immune deficiency can be readily recognized based on clinical hallmarks early recognition will allow determination of the specific immunologic defect & will spare the patient unnecessary tests & will prevent complications

2006 MWS

Summary although treatment may appear costly in the beginning, institution of appropriate treatment protocols will lead to cost-effective treatment, prolonged & better quality of life, & less frequent use of antibiotics

2006 MWS

Documents

Allergy 2011