Asthma

• 23 year old female with history of allergic rhinitis complains of dyspnea and chest tightness worse with exertion

• 65 year old male with 35 pack year history of smoking complains of cough with sputum expectoration and limitations in activity.

• What’s the diagnosis for the above cases?

Despite progress in understanding the mechanisms of asthma,much is obscure

Asthma is a syndrome of signs, symptoms, and lab abnormalities but probably represents multiple diseases

Clinical diagnosis is based on history of cough, wheeze, dyspnea, and reversible airway obstruction

Our understanding of its pathogenesis is best worked out for allergic asthma: but much asthma is not identifiably allergic “intrinsic asthma”

Defining features of asthma

• Variable airflow obstruction

• Airway hyper responsiveness to a variety of stimuli

• Inflammation in the airway

Risk factors for asthma

• ATOPY

• AGE

• ENGLISH LANGUAGE SPEAKING COUNTRIES

• FAMILY HISTORY OF ASTHMA

• 60% GENETIC BASIS IN IDENTICAL TWINS

AIRWAY INFLAMMATION IN ASTHMA

• THICKENING OF BASEMENT MEMBRANE

• INCREASED SMOOTH MUSCLE MASS

• SLOUGHING OF PSEUDOSTRATIFIED EPITHELIUM

• INCREASED GOBLET CELLS

• SUBMUCOSAL INFLAMMATION WITH EOSINOPHILS, • LYMPHOCYTES, AND EDEMA

• INCREASED VASCULARITY

MICROSCOPIC ANATOMY OF ASTHMA

ALLERGIC MODEL FOR ASTHMA

• AEROALLERGEN EXPSOSURE TRIGGERS SPECIFIC IGE AB

• OVEREXPRESSION OF TH2 TYPE T CELL RESPONSE

• IGE AB BIND TO SURFACE RECEPTRS ON MAST CELLS

• RE-EXPOSURE TO ALLERGEN LEADS TO CROSS LINKING OF IGE ANTIBODIES TRIGGERING MAST CELL DEGRANULATION AND MEDIATOR RELEASE

EARLY PHASE REACTION: WITHIN MINUTES

• SMOOTH MUSCLE CONTRACTION WITHIN SMALL AND LARGE AIRWAYS PRODUCES RAPID INCREASE OF AIRWAY RESISTANCE

• INFLAMMATION RESULTS IN COUGH, MUCOUS RELEASE

• AIRWAY RESISTANCE RESULTS IN TACHYPNEA, TACHYCARDIA, HYPERINFLATION OF LUNGS, SEVERE INCREASE IN WORK OF BREATHING, FALL IN ALL AIR FLOW PARAMETERS

• MEDIATORS: HISTAMINE,PROSTAGLANDINS D2, CYSTEINYL LEUKOTRIENES (LTC4, D4, AND E4)

LATE PHASE REACTION:4-6 HRS. LATER

• COINCIDES WITH INFLUX OF T LYMPHOCYTES, EOSINOPHILS AND BASOPHILS

• PLETHORA OF MEDIATORS ARE RELEASED

• EOSINOPHIL FACTORS: LEUKOTRIENES, PAF,MAJOR BASIC PROTEIN,PEROXIDASE,EOSINOPHILIC CATIONIC

• PROTEIN,GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR,TRANSFORMING GROWTH FACTOR, INTERLEUKINS

Other players in the late phase reaction

• MAST CELLS:HISTAMINE, PROSTAGLANDINS, LEUKOTRIENES,TNF ALPHA

• TH2 LYMPHOCYTES:CYTOKINES o: 3,4,5,13, GM-CSF, CHEMOKINE RECPTORS

• NKT CELLS MAY MODULATE INFLAMMATION

• BASOPHILS: HISTAMINE, LEUOTRIENES, IL 11 AND 13.

• INNATE IMMUNE SYSTEM, AND EPITHELIALA AND MESENCHYMAL CELLS MAY ALSO PARTICIPATE

MECHANISMS OF AIRWAY OBSTRUCTION

• CONTRACTION OF AIRWAY SMOOTH MUSCLE

• THICKENING OF AIRWAYS DUE TO EDEMA AND INFLAMMATORY CELLS

• PLUGGING OF AIRWAYS WITH MUCOUS AND CELLULAR DEBRIS

• AIRWAY REMODELING

AIRWAY HYPER-RESPONSIVENESS

• EXERCISE

• IRRITANTS IN AIR: SMOKE, PERFUME, CLEANING SUBSTANCES

• DRUGS SUCH AS METHACHOLINE

• COLD AIR

TYPES OF ASTHMA

• CHILDHOOD ASTHMA VS. ADULT ASTHMA

• ALLERGIC ASTHMA VS. INTRINSIC ASTHMA

• OCCUPATIONAL ASTHMA

• EXERCISE INDUCED ASTHMA

• ASPIRIN INDUCED ASTHMA

• COUGH EQUIVALENT ASTHMA

• FACTITIOUS ASTHMA

DIAGNOSIS OF ASTHMA

• HISTORY OF EPISODIC COUGH, WHEEZE, DYSPNEA, CHEST TIGHTNESS, ESPECIALLY AT NIGHT

• HISTORY OF TWITCHY LUNGS: EXCESSIVE RESPONSE TO EXERCISE, COLD AIR, ALLERGENS, POLLUTANTS, UPPER AIRWAY INFECTIONS, FUMES, ODORS

• DOCUMENTATION OF REVERSIBLE AIRWAY OBSTRUCTION

• Eosinophil counts >5%, sputum eosinophilia or examination of sputum for asthmatic elements occasionally helpful

NATURAL HISTORY OF ASTHMA

• CHILDHOOD ASTHMA TENDS TO REGRESS IN THE TEENS BUT MAY RECUR AS AN ADULT

• ADULT ONSET ASTHMA IS USUALLY PERSISTENT

• SEVERE CHILDHOOD ASTHMA TENDS TO PERSIST

• ABOUT 30% OF INDIVIDUALS EXPERIENCE REMISSION

• UNKNOWN % PROGRESS TO IRREVERSIBLE OBSRUCTION

• U.S. PREVALANCE: ABOUT 8% OF POPULATION

ASTHMA AND THE WORLD

• WIDE RANGE OF ASTHMA :3.4% IN AFRICA,5.1% EASTERN EUROPE, UP TO 25% IN ENGLISH LANGUAGE COUNTRIES

• HIGHEST U.S. INCIDENCE IN PUERTO RICO

• OVERALL TREND TO INCREASED INCIDENCE IN U.S. AND WORLDWIDE

• OVERALL ASTHMA MORTALITY WAXES AND WANES

HYGIENE HYPOTHESIS

• WESTERN HOME HYGIENE MAY RESULT IN DELAY OF EXPOSURE TO DIRT,BACTERIA, PARASITES,MOLDS .

• LATE EXPOSURE MAY TRIGGER HIGHER INCIDENCE OF ALLERGIES/ASTHMA

• CHILDREN RAISED ON FARMS MAY HAVE HALF THE INCIDENCE OF ASTHMA SEEN IN URBAN CHILDREN

MEDIATORS OF ACUTE ASTHMA RESPONSE

• ACETYLCHOLINE FROM PULMONARY NERVE ENDINGS• HISTAMINE: FROM MAST CELLS• KININS:MAST CELLS-KALLIKREIN-CLEAVES BRADYKININ FROM

PLASMA PRECURSORS• LEUKOTRIENES AND LIPOXINS: MAST

CELLS,EOSINOPHILS,MACROPHAGES• NEUROPEPTIDES: FROM NERVE ENDINGS• NO:EPITHELIAL CELLS,INFLAMMATORY CELLS:MARKER OF

ASTHMA• PAF: MAST CELLS, EPITHELIAL CELLS

ROLE OF VIRUSES

• ONSET OF ASTHMA OFTEN FOLLOWS VIRUS ILLNESS

• RSV INFECTIONS MIMIC ASTHMA AND MAY BE FOLLOWED BY PERSISTENT ASTHMA

• >50% EXACERBATIONS TRIGGERED BY VIRAL ILLNESS

PHYSIOLOGY OF ACUTE ATTACK

• RAPID RISE OF AIRWAY RESISTANCE

• IMMEDIATE INCREASE IN DEAD SPACE, TLC,DECREASED ELASTIC RECOIL, TIDAL BREATHING AT HIGH VOLUME

• MARKED INCREASE IN PLEURAL PRESSURE:PULSUS PARADOXICUS

• TACHYPNEA

• MARKED INCREASED WORK OF BREATHING TRIGGERS MUSCLE FATIGUE

GAS EXCHANGE EFFECTS

• PATCHY AIRWAY CLOSURE RESULTS IN HIGH VARIABILITY OF V/Q RATIOS AND HYPOXEMIA

• HYPERVENTILATION AND RESP. ALKALOSIS IS USUAL RESPONSE

• SEVERE ATTACKS ONLY: EUCAPNEA OR HYPERCAPNEA

• VERY SEVERE ATTACKS:COMBINED RESP./METABOLIC ACIDOSIS

EXTRINSIC (ALLERGIC)ASTHMA

• MOSTLY IN CHILDHOOD

• ASSOCIATED WITH ATOPY,ECZEMA,FAMILY HISTORY

• ENVIRONMENTAL TRIGGERS: HOUSE DUST MITE, PETS,ROACHES,SEASONAL ALLERGIC ATTACKS WITH POLLENS, MOLDS

• POSITIVE SKIN TEST

• POSITIVE RAST ANTIBODIES

INTRINSIC ASTHMA

• ADULT ONSET

• NON-SPECIFIC TRIGGERS: VIRUSES,COLD AIR,EXERCISE, FUMES,AIR POLLUTION: OFTEN NOT IDENTIFIABLE

• NEGATIVE SKIN TESTS AND RAST TEST

• NON-SEASONAL

OCCUPATIONAL ASTHMA

• LAB ANIMALS,CHICKENS, CRABS, PRAWNS, OYSTERS

• GRAIN DUST, WHEAT FLOUR,GUM ACACIA

• BIOLOGIC ENZYMES; TRYPSIN,PEPSIN, B. SUBTILIS

• METALS:PLATINUM, VANADIUM

• MISCELLANEOUS (>100):Toluene di-isocyanate in plastics,epoxy resins, Western red cedar, formalin, urea, formaldehyde (insulation)

TREATMENT OF ASTHMA

• CORRECT DIAGNOSIS

• CATEGORIZE SEVERITY:INTERMITTENT; PERSISTENT: MILD, MODERATE, OR SEVERE

• OBJECTIVE PHYSIOLOGIC MEASUREMENT(SPIROMETRY,PEAK FLOW)

• EDUCATE PATIENT: PARTNERSHIP IN CARE

• IDENTIFY AND AVOID RISK FACTOTRS

• INDIVIDUAL MEDICATION PLAN AND FOLLOW-UP

SEVERITY OF ASTHMA

• INTERMITTENT: SYMPTOMS<1x/week, nocturnal symptoms<2x/mo.,Peak Flow>80% predicted,<20% variability

• MILD PERSISTENT: symptoms>1x/wk<daily,nocturnal symptoms>2x/mo;attacks affect activity,PF>80% but 20-30% variability

• MODERATE PERSISTENT: daily symptoms, nocturnal symptoms >1x/wk,attacks affect activity,PF60-80% with >30% variability

• SEVERE PERSISTENT:continuous symptoms,limited physical activity,PF<60% with >30% variability

DRUGS FOR ASTHMA: CONTROLLERS

• CORTICOSTEROIDS: INHALED OR SYSTEMIC

• LONG ACTING BETA AGONISTS:FORMOTEROL, SALMETEROL,OTHERS

• ANTILEUKOTRIENES: MONTELEUKAST (SINGULAIR),ZAFIRLEUKAST (ACCOLATE), ZILEUTON

• SUSTAINED RELEASE THEOPHYLLINES

• SODIUM CROMOGLCYATE, NEDOCROMIL

• ANTI-IGE DRUG:OMALIZUMAB (XOLAIR)

DRUGS FOR ASTHMA: RELIEVERS

• SHORT ACTING BETA AGONISTS: ALBUTEROL,LEVALBUTEROL,PIRBUTEROL,METAPROTERENOL,TERBUTALINE,ISOETHARINE,EPINEPHRINE

• ANTICHOLINERGICS:IPRATROPIUM, LONG ACTING TIOTROPIUM

• SHORT-ACTING THEOPHYLLINE

• EPINEPHRINE INJECTION OR TERBUTALINE INJECTION

STEPWISE TREATMENT

• INTERMITTENT: pt. education, PF meter, albuterol MDI

• MILD PERSISTENT: Low dose inhaled steroid +- leukotriene blocker, sustained dose theophylline, cromolyn

• MODERATE PERSISTENT: low to medium dose inhaled steroid, leukotriene blocker or cromolyn, consider long acting beta agonist for limited period, consider theophylline

• SEVERE PERSISTENT: high dose inhaled steroid, long acting beta agonist+- anticholinergic,theophylline, leukotriene blocker, systemic steroids

ALLERGY MANAGMENT

• AVOIDANCE WHERE POSSIBLE

• HYPOSENSITIZATION THERAPY

• ENVIRONMENTAL CONTROLS

EKG in ASTHMA

• SINUS TACHYCARDIA

• RARELY CHANGES OF ACUTE RIGHT VENTRICULAR OVERLOAD: RAD,RBBB, P PULMONALE, NON SPECIFIC ST CHANGES

CHEST X RAY IN ASTHMA

• HYPERINFLATION IS USUAL CHANGE• RARELY PNEUMOTHORAX,

PNEUMOMEDIASTINUM OR PNEUMOPERICARDIUM

• BRONCHIECTASIS CHANGES IN ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS WITH MUCOID IMPACTIONS VISIBLE

CHEST X RAY IN ASTHMA

ASTHMA PLAN FOR EVERY PATIENT

• DRUG LIST• MONITORING PLAN AND GUIDELINES FOR

CHANGES IN THERAPY• EMERGENCY NUMBERS• INSTRUCTIONS ON WHAT TO DO FOR

WORSENING ASTHMA, WHEN TO PHONE, WHEN TO CALL AMBULANCE, WHEN TO ADJUST THERAPY

BASIC MANAGEMENT OF THE ASTHMA PATIENT

• SEE WITH FREQUENCY DICTATED BY INDIVIDUAL PATIENT HISTORY AND RISKS

• ASSESS PULMONARY FUNCTION AND SYMPTOMS AT EVERY VISIT

• MAKE SURE PATIENT IS GETTING AND TAKING MEDICATIONS

• REVIEW STATUS SINCE LAST VISIT: TRIGGERS, NOCTURNAL SYMPTOMS, EXERCISE, WORK, MISSING SCHOOL. FREQUENCY OF USE OF SHORT ACTING BRONCHODILATORS

The difficult asthmatic• FAILURE TO TAKE CONTROLLER DRUGS REGULARLY IS

MAJOR CAUSE• REVIEW TRIGGERS; GO BACK OVER HISTORY• CONSIDER CORTICOSTEROID RESISTANCE• CHECK TECHNIQUES FOR USING INHALERS• LOOK FOR SINUSITIS, GERD, AGGRAVATING

MEDICATIONS• CONSIDER ALLEERGY TESTING• CONSISDER ALLERGIC BRONCHOPULMONARY

ASPERGILLOSIS• REVIEW OCCUPATIONAL FACTORS• CONSIDER FACTITIOUS ASTHMA, AND UNDIAGNOSED

UPPER AIRWAY OBSTRUCTION

RISK FACTORS FOR SEVERE ASTHMA

• PRIOR MECHANICAL VENTILATION OR ICU ADMISSION• 2 OR MORE HOSPITALIZATIONS IN LAST 12 MONTHS• 3 OR MORE ED VISITS IN LAST YEAR• HOSPITALIZATION OR ED RX WITHIN 1 MONTH• USE OF MORE THAN 2 CANISTERS OF SHORT ACTING

BETA AGONIST/MO• REQUIREMENT FOR ORAL PREDNISONE• PSYCHIATRIC OR BEHAVIOR ISSUES; COMORBIDITIES

THERAPY OF THE ACUTE ATTACK

• SHORT ACTING ALBUTEROL: 4 PUFFS Q 10 MINUTES WITH SPACER OR 5 MG.BY CONTINUE FLOW NEBULIZATION Q. 30 MINUTES

• LOW FLOW OXYGEN• STEROIDS: EITHER 60 MGM. PREDNISONE P.O. OR

STANDARD DOSE iv SOLUMEDROL• IPRATROPIUM IS A USEFUL ADD ON• CONSIDER MAGNESIUM SULFATE 2 G. OVER 20 MINUTES

IV• POSSIBLE THEOPHYLLINE USE (EVIDENCE MIXED ON

THIS)