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
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 symptomsSampson 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 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
10 Warning Signs of Primary ImmunodeficiencyThe Jeffrey Modell Foundation
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
10 Warning Signs of Primary ImmunodeficiencyThe Jeffrey Modell Foundation
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
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