Four Types of Hypersensitivity Reaction

Type I

Type II

Type III

Type IV

Type I Hypersensitivity
allergen

Fc receptor

mast cell degranulation mediator release

Type II Hypersensitivity
K
target cell

cytotoxic action
antibody
complement target cell

complementmediated lysis

Type III Hypersensitivity

immune-complex deposition

complement

tissue basement membrane

Blood Vessel

Type IV Hypersensitivity
antigens T inflammatory mediators

lymphokines

activated macrophage

ALLERGIC PROCESS

Pathophysiology of Type I Allergic Reaction Sensitization Phase:

Initial antigen exposure

Internalization
Antigen-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

Internalization
Antigen-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 Response

An t ige n Na s al e pit h el ium

Sne eze /I t ch
A 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 Response

Antigen 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 Mediators

Early Phase

Late Phase

ALLERGIC PROCESS
Mast-cell activation & physiological effects of mast-cell derived mediators

ALLERGIC DISEASES
HIYASMIN M. LIM, M.D.

APPROACH TO DIAGNOSIS
I.

ALLERGIC HISTORY PHYSICAL EXAMINATION

II.

III.
I. II.

LABORATORY PROCEDURES
CBC 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 TEST
VII.

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

Internalization
Antigen-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

Internalization
Antigen-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 RHINITIS
Typical Symptoms: sneezing clear rhinorrhea nasal itching nasal congestion reversible, spontaneously or with treatment

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

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

ALLERGIC RHINITIS

Facial Grimace

ALLERGIC RHINITIS

Allergic Hand Salute

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

ALLERGIC RHINITIS

Allergic Shiners

ALLERGIC RHINITIS
Signs / 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 Rhinitis

Intermittent symptoms < 4 days per week or <4 weeks
Mild normal sleep normal daily activities, sport, leisure normal work and school no troublesome symptoms

Persistent symptoms > 4 days / week and >4 weeks

Moderate-Severe
one 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

ANAPHYLAXIS
HIYASMIN M. LIM, M.D.

Definition
Anaphylaxis 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.

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 anaphylaxis

Anaphylaxis

Allergic anaphylaxis

Non-allergic anaphylaxis

IgE- mediated anaphylaxis

Immunologic, non-IgEmediated anaphylaxis

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

Epidemiology
o

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

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 anaphylaxis
Oral:
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 anaphylaxis
o

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

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

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

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

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

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 <90mmHg or >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: Immediate

o o o o

RAPID recognition ABCs of resuscitation Epinephrine

O2 100% and secure and maintain airway

Physician-supervised management of anaphylaxis

II. 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 anaphylaxis

III. Other measures:

a)

epinephrine 1:1000, dose (0.1- 0.2 mg) into reaction site

diphenhydramine, 50 mg IV or orally (1.25 mg/kg, up to 50 mg dose for children); maximum daily dose: adults 400 mg; children

200 mg
b) 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 for

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

Physician-supervised management of anaphylaxis

o

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

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

Complications
o

Death
o

Laryngeal edema, respiratory failure, shock, cardiac arrhythmia

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

Long Term Management

o
o

Risk assessment
Risk reduction strategies (personalized) Anaphylaxis education

Prevention of Anaphylaxis in community setting

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 children<3 years of age and approximately 2% of adults experienced food induced allergic disorder. 35% with moderate to severe atopic dermatitis food allergy 6% with bronchial asthma food allergy

Clinical Disorders
Gastrointestinal Cutaneous Respiratory Generalized anaphylaxis Food-associated Exercise-induced anaphylaxis

GASTROENTINTESTINAL HYPERSENSITIVITY DISORDER IgE Non -IgE

Immediate GI hypersensitivity Oral Allergy Syndrome Allergic Eosinophilic Esophagitis Allergic Eosinophilic Gastritis Allergic Eosinophilic Gastroenteritis Enterocolitis Dietary protein Dietary protein proctitis Dietary Protein Enteropathy celiac Disease

Cutaneous Hypersensitivity Disorder

IgE Non IgE

Acute Urticaria /Angioedema Acute Contact Urticaria Chronic Urticaria Angioedema

Atopic Dermatitis

Dermatitis Herpetiformis

Respiratory Hypersensitivity Disorder

IgE Non IgE

Allergic Rhinitis Acute Bronchospasm Asthma

Food Induced Pulmonary Hemosiderosis

GENERALIZED REACTIONS
Anaphylaxis Food-associated exercise-induced anaphylaxis

DIAGNOSIS OF FOOD ALLERGY

Medical History and Physical Examination Diet Diary Elimination Diet Laboratory Skin test - Prick Skin Test - Prick Prick test - RAST; CAP System Food Challenge - Open - Single/ Double Blind

PHYSICAL EXAMINATION
Nasal Findings: Edema, mucus, color of mucous. Ocular Findings: Edema, Chemosis Oral Findings : Edema Chest Sign: Cough, Wheezing, rhonchi Abdominal Signs: Tenderness, altered bowel sounds Skin Findings : Signs of atopic dermatitis, occasional urticaria

CURRENT METHODS OF MANAGEMENT OF FOOD ALLERGY

I. Avoidance II. Medication Antihistamine Corticosteroid Cromolyn Ketotifen Prostaglandins Inhibitors Leukotriene Modifiers

URTICARIA

Hiyasmin Medillo-Lim, M.D.

Urticaria: Wheals &/or angioedema

Definition: Urticaria is a heterogeneous group of diseases which share a common distinctive reaction pattern resulting in the development of urticarial skin lesions (wheals) and/or angioedema. EAACI/GA2LEN/EDF/WAO Position Paper, Allergy 2009

Urticaria: Wheals &/or angioedema

Definition: WHEAL consists of three typical features: 1. A central swelling of variable size, almost invariably surrounded by a reflex erythema 2. Associated itching or sometimes burning sensation 3. A fleeting nature, with the skin returning to its normal appearance usually within 1-24hrs EAACI/GA2LEN/EDF/WAO Position Paper, Allergy 2009

URTICARIA

Pruritic raised erythematous blanching circumscribed lesions in the superficial portion of the dermis

urticaria

Urticaria: Wheals &/or angioedema

Definition: ANGIOEDEMA: characterized by 1. Sudden pronounced swelling of the lower dermis and subcutis 2. Pain rather than itching 3. Frequent involvement below the mucous membranes 4. Resolution slower than wheals, up to 72hrs EAACI/GA2LEN/EDF/WAO Position Paper, Allergy 2009

ANGIOEDEMA
Deeper

cutaneous swelling, less circumscribed, less pruritic, more of tingling or burning sensation

Epidemiology of Urticaria

Urticaria affects up to 20% of the population at some time in a lifetime

Transitory (individual episodes < 24h duration) red skin swellings with itching No desquamation, rarely affects mucous membranes

Associated with angioedema in about 40% of cases

Classification of Urticaria
Types Spontaneous urticaria Subtypes Acute spontaneous urticaria Chronic spontaneous urticaria Cold contact urticaria Delayed pressure urticaria

Physical urticaria

Heat contact uricaria Solar urticaria Urticaria factitia/ dermographic urticaria

Vibratory urticaria

Other urticaria types

Aquagenic urticaria Cholinergic urticaria

Contact urticaria Exercise induced anaphylaxis/urticaria

Classification of Urticaria Subtypes

I. Spontaneous Urticaria: ACUTE spontaneous urticaria: Spontaneous wheals and/or angioedema <6weeks CHRONIC spontaneous urticaria: Spontaneous wheals and/or angioedema >6weeks

Acute urticaria

All ages; common in childhood Abrupt onset of urticarial eruption usually pruritic and widespread Angioedema common

Systemic symptoms (fever, malaise) also common, depending on cause

Duration: usually hours or days

Zuberbier T, Ifflander J, Semmler C, et. al. Acta Derm Venereol 76:295-297, 1996.

Causes of acute urticaria

Viral infections; particularly in children. In adults: prodrome of Hepatitis B, infectious mononucleosis (EBV) Drugs (NSAIDS, penicillins and derivatives, radiocontrast media) Foods nonallergic (e.g., scombroid fish poisoning) and allergic (IgEmediated) (e.g., nuts, shellfish)

Immunization vaccines e.g., MMR, tetanus toxoid

Investigation of acute urticaria

Many cases require no investigation - the cause is evident to patient and doctor alike Skin prick tests may support the diagnosis (but avoid SPT in severely affected patients, and in patients with current angioedema or a history of angioedema) Serum IgE testing may also help confirm the culprit

Classification of Urticaria Subtypes

II. Physical Urticaria: COLD contact urticaria: cold objects/air/fluids/wind DELAYED pressure urticaria fr vertical pressure, arising with 3-12hr latency HEAT contact urticaria localized heat SOLAR urticaria UV and or visible light VIBRATORY urticaria/angioedema vibratory forces/pneumatic hammer

Classification of Urticaria Subtypes

II. Physical Urticaria:

Urticaria FACTITIA/ dermographic urticaria mechanical shearing forces; arising after 1-5mins

Classification of Urticaria Subtypes

III. Other Urticaria types: AQUAGENIC urticaria water CHOLINERGIC urticaria incr in body temp from exercise/spicy food CONTACT urticaria contact with urticariogenic substance EXERCISE induced urticaria physical excercise

Recommended diagnostic tests for frequent Urticaria Subtypes

I. Spontaneous Urticaria: ACUTE spontaneous urticaria: NONE CHRONIC spontaneous urticaria: CBC with ESR/CRP omission of suspected trigger/drug

Recommended diagnostic tests for frequent Urticaria Subtypes

I. Spontaneous Urticaria: CHRONIC spontaneous urticaria: infectious diseases: h pylori type 1 allergy: skin prick test functional autoantibodies thyroid hormones and autoantibodies pseudoallergen free diet tryptase ASST skin biopsy

Recommended diagnostic tests for frequent Urticaria Subtypes

II. PHYSICAL Urticaria: COLD contact urticaria: cold provocation: ice cube DELAYED pressure urticaria pressure test 0.2-1.5kg/cm2 for 10, 20 mins HEAT contact urticaria heat provocation SOLAR urticaria UV and or visible light of diff wavelengths VIBRATORY urticaria/angioedema pneumatic hammer/cetrifuge

Recommended diagnostic tests for frequent Urticaria Subtypes

III. Other Urticaria types: AQUAGENIC urticaria wet cloths at body temp for 20mins CHOLINERGIC urticaria exercise and hot bath CONTACT urticaria prick/patch test then read after 20mins Exercise induced urticaria perform specific exercise

Chronic Urticaria
It is unusual to find exogenous cause for chronic urticaria.

Unknown pathogenesis (50%) Autoantibodies against the subunit of the high-affinity IgE receptor (Fc RI) (about 40%) Autoimmune: IgG anti-IgE autoantibodies (5%)

Pathogenesis of CIU

Reaction to food additive, dye or preservative (5%)

Management of Urticaria
The AIM of treatment is the same for ALL types urticaria: To achieve complete symptom control.
Management is best divided into 2 basic lines of approach: The identification and elimination of the underlying cause(s) and or eliciting trigger

The treatment aimed at providing symptom relief: currently the most frequently used for of management

Treatment algorithm
EAACI/GA2LEN/EDF/WAO Position Paper, Allergy 2009

Cholinergic urticaria

Cold urticaria

Dermatographism

ATOPIC DERMATITIS

ATOPIC DERMATITIS
Chronic,

relapsing, highly pruritic inflammatory skin disease Frequently precedes asthma/allergic rhinitis most common chronic skin disease of young children

ATOPIC DERMATITIS
Occurs

in 3-5 % of the population up to age 5 years, possibly up to 10%

Prevalence

has continued to increase

Environmental

factors are critical in disease expression

ATOPIC DERMATITIS
85% 90% Adult

of cases present in first year of life of cases develop by 5 years of age

onset AD should raise a higher index of suspicion for other diseases

ATOPIC DERMATITIS
No

specific clinical or laboratory diagnostic markers

Diagnosis

based on clinical findings

ATOPIC DERMATITIS
Infantile Stage: ( birth - 2 years ) dry,red scaly plaques

scalp face ( cheeks, chin ) trunk extensor surfaces of the extremities

Headlight sign

ATOPIC DERMATITIS
Childhood Stage: ( 2 - 12 years ) papules that coalesce plaques

flexural areas

antecubital popliteal neck wrists ankles

ATOPIC DERMATITIS
Adolescent and Adult Phase: ( >12 yrs ) increased scaling decreased excoriation

flexural areas dorsum of hand

Hanifin and Rajka Criteria

MAJOR CRITERIA:

pruritus chronic or relapsing course personal or family history of atopy typical distribution of dermatitis facial and extensor surfaces in children<2 flexural involvement in children >2 or adults

PRURITUS

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

Hanifin and Rajka Criteria

MINOR CRITERIA: early age of onset xerosis ( dryness ) facial pallor or erythema infraorbital darkening white dermographism

Hanifin and Rajka Criteria

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

Hanifin and Rajka Criteria

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

Hanifin and Rajka Criteria

MINOR 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 barrier
Decreased skin ceramide levels

Decreased water binding

Imokawa 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 Reactions

C3a, C5a

Mast cell

Arachidonic acid

Opiates Vancomycin Curare

RCM

Lipoxygenase

Cyclooxygenase

IVIG

Leukotrienes

Prostaglandins

Aspirin NSAIDs

00

Drug Allergy: Definition

Immunologically

mediated reactions to drugs or its metabolites

Immunopathology of Drug Allergy

Gell & Coombs Classification Immunoreactants Clinical presentation

Type I
RBC

Anaphylaxis
IgG or IgM

Type I I

Immune cytopenias Serum sickness

Contact dermatitis

Type III Type I V

TH CD4

IgG

Modified Gell & Coombs Type IV Reaction

Types
Cells & Mediators involved
IFN-g TNF APC TH1 IL-5 IL-4, 13 TH2
Granzymes Perforins

Associated Reactions Examples

Ab 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 c
IV 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-PGH

Others 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 illnesses
137

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 drugs

Generalized or multisystem involvement
Immediate 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 drugs

Reaction predominantly organ specific
Dermatologic manifestation Pulmonary manifestation Hematologic manifestation Hepatic manifestations Renal manifestations Lymphoid system manifestations Cardiac manifestations Neurologic manifestations

Evaluation of patients with suspected drug hypersensitivity

Detailed 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 hypersensitivity

In 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 Hypersensitivity

1.

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 CONTROL

CHARACTERISTIC CONTROLLED
DAYTIME SYMPTOMS LIMITATION OF ACTIVITIES NOCTURNAL SYMPTOMS AWAKENING
NEED 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 Exacerbations

MILD
Breathless 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/min
Philippine Consensus for the Management of Childhood Asthma 2002

Assessment of Severity of Asthma Exacerbations

Clinical features:

MILD
Accessory muscles and suprasternal retractions

MODERATE

SEVERE

RESP. ARREST IMMINENT

Present 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 Exacerbations

Objective Measures:

MILD
PEF % 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 adolescents
Philippine 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 test
III. 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, MD
2006 MWS

Immune Response
Complex 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 System

DEFENSE

Resistance to infection

HOMEOSTASIS

Removal of worn out self

Perception 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 pathogen

No

prior exposure needed

Resistance

not improved by repeated infecton

2006 MWS

Adaptive Immune Response

SPECIFIC
SOLUBLE Antibodies (Humoral immunity)
CELLULAR T-lymphocytes (Cell-mediated immunity) CHARACTERISTICS
Subsequent

encounters with pathogen needed

Need

previous exposure and recognition (Self and Non-Self)

Resistance

improved by repeated infection

2006 MWS

ANTIGENIC STIMULUS
IMMUNE RESPONSE NON-SPECIFIC
Phagocytosis Inflammation

TOLERANCE

SPECIFIC

HUMORAL
2006 MWS

CELL-MEDIATED

IMMUNOPATHOLOGY
AUTOIMMUNITY

Failure of appropriate recognition

HYPERSENSITIVITY

Overactive immune response

IMMUNODEFICIENCY

Failure to produce an adequate immune response

2006 MWS

Definition
Immunodeficiency 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 Immunodeficiency

The 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

10 Warning Signs of Primary Immunodeficiency

The Jeffrey Modell Foundation

Failure of an infant to gain weight or grow normally

2006 MWS

Recurrent, deep skin or organ abscesses

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

10 Warning Signs of Primary Immunodeficiency

The Jeffrey Modell Foundation

Need for intravenous antibiotics to clear infections

2006 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: 10,000
Phagocytic 18%
Complement 2%

Frequency
Italy 1:77,000 Japan 1:200,000 Switzerland 1:54,000 Sweden 1:55,000

Cellular
10%

Combined 20%

Antibody 50%

AAAAI 2000
2006 MWS

The Spectrum of Infection Associated with Different Forms of Immune Deficiency Disease
Immune Deficiency Disease
B cell (Antibody) Deficiency T cell/Combined Deficiency Phagocyte Deficiency Complement Deficiency
2006 MWS

Bacterial

Type of Infection Viral Fungal

Protozoal

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

+ +++ -

+++ ++

+ +++ -

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

2006 MWS

Serum Ig in Newborns

2006 MWS

Diagnosis
Tests 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 Presentation
T cell / Combined Immune Deficiency Disorders presentation in first 6 months failure to thrive recurrent/chronic diarrhea recurrent candidiasis other opportunistic infections

2006 MWS

Diagnosis
Tests of T-lymphocyte Function
Initial
Total lymphocyte count
( Lymphopenia < 1500 cells )

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

2006 MWS

Diagnosis
Tests of Phagocytic Function
Initial
Nitroblue Tetrazolium Reduction Test (NBT) Rebuck Skin Window WBC count / morphology

Advanced
Phagocytic assay Chemotaxis assay Bactericidal assay Neutrophil oxidative burst

2006 MWS

Clinical Presentation
Complement 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 Signs

Detailed Hx & PE Infections confined to a single organ system

YES

NO

Otherwise good health

Generally poor health

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

SYSTEMIC
Identify 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 AIDS
Suspect 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