ASTHMA

Gene R. Pesola, M.D., M.P.H. Dept. of Pulmonary/Critical Care Medicine

Definition - Asthma
ATS 1962 Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and manifested by a widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy.

Definition - Asthma
Practical Clinical Definition of Asthma The office definition. Someone who wheezes on clinical examination and improves with a bronchodilator. Ideally a chest x-ray is obtained and is normal. Has a hx of recurrent wheezing over time.

Definition - Asthma
Chronic lung disease with 3 characteristics:
1. Reversible airway obstruction usually. 2. Airway inflammation. 3. Increased airway responsiveness to a multiplicity of stimuli.

Definition - Asthma
Research Definition Current Asthma 1. History of asthma with wheezing. 2. Minimal smoking history. 3. And either demonstrated airway reversibility with B.D. or a drop in FEV1 of 20% with a methacholine challenge.
Pesola GR, Dogra S, Coelho-DCosta V. The diagnosis of Current Asthma for the research asthmatic. Internet Journal of Asthma, Allergy, and Immunology, 2002:2(2).

Methacholine Challenge Test

60
FEV1 (% change)

50 40 30 20 10 0
1 25 4 16 64 0. 25 6

Asthmatic Mild Asthmatic Normal

Concentration (mg/ml)

Epidemiology - Asthma
What is the prevalence of asthma?
Estimated at 6-7% in the U.S. Allergic diseases including asthma seem to be increasing markedly in this day and age.

The Asthma Epidemic

20 Millions of 10 Cases 0 8.5 17

1 1980

2 1998

Asthma Trends
A child born a generation from now is twice as likely to develop asthma as one born today, if current trends continue.

The Hygiene Hypothesis

Theory: a lack of early exposure to dirt, bacteria, and other infectious agents can lead to abnormalities of the immune system that promote the development of allergies, which then predispose to allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis.

Protective Immunity/Allergic Disease Cytokine Balance

TH1 phenotype
Older siblings Early exposure to day care (< 6 months) TB, hepatitis A, or measles infection Rural environment

TH2 phenotype (atopic)

Overuse of antibiotics Western lifestyle Urban environment Diet Sensitization to housedust mites & cockroaches

THo Lymphocyte In Utero

IFNTH1 NonAllergic IL-12 IFN-

PGE2 placenta progesterone IL-4 TH2 Atopic At Birth

macrophage
TB

IL-12

TH1

TH2 First 2 years

= inhibitory

Epidemiology - Asthma
What is the prevalence of asthma?
Estimated at 6-7% in the U.S. Depends on how you ask the question.

Epidemiology - Asthma
Q. Do you have asthma?
1995 - 14.8 million with asthma 1996 - 14.6 million with asthma

14.7 mil/260 mil x 100 = 5.7%

Epidemiology - Asthma
New Q. Has a doctor or other health care provider ever said you have asthma? 1999 24.7 million dx with asthma (9.5%) New Q. Have you had an asthma attack in the last year? 1999 10.5 million had an asthma attack in the last year (4.0%).

Asthma Distribution by Gender, 1999, 10,488,284 asthmatics

41% 59%

female

male

Asthma Distribution by Age, 1999, 10,488,284 asthmatics

7% 19% 28% 8%

< 5 years 5-17 years 18-44 years 45-64 years >65 years

38%

Asthma Distribution by Race, 1999, 10,488,284 asthmatics

7% 15% white black other

78%

Asthma Deaths 1980-1999

6000 5000
Asthma Deaths

4000 3000 2000 1000 0

0 19 8 19 9 5

Total Deaths Female Deaths Male Deaths

Age Adjusted Death Rate per 100,000 population

Age Adjusted Death Rate/100,000

2.5 2 1.5 1 0.5 0

1980 1990

Total Female Male

Age-adjusted death rate 1997, adjusted to the standard 1940 population

Rank
1 2 3 4 5 6 7 8 9

Cause
Heart Disease Cancer Stroke COPD Accidents Pneumonia/Influenza Diabetes Mellitus Suicide Renal Disease

Rate
130.5 125.6 25.9 21.1 30.1 12.9 13.5 10.6 4.4

10

Chronic Liver Disease

7.4

Economic Burden - Asthma

Total Cost 1999 about 12.7 billion Direct cost - 8.1 billion
Hospitalization 3.5 billion ED visits (2 mil/yr) 0.7 billion Medication 2.5 billion Indirect cost 4.6 billion

Pathophysiology - Asthma
Genetic Background (atopy) Environmental Risk Factors allergens, infections, diet, pollutants

Airway Inflammation
Airway hyperresponsiveness Airflow limitation

Symptoms

Genetics - Asthma
Twin studies Monozygotic (MZ) 100% Dizygotic (DZ) 50% Self-reported MZ concordance asthma 19% & DZ 4.8%. Environmental some MZ are not concordant.

Genetics - Asthma
ASTHMA

Atopy AH

Genetics - Asthma
Not simple single gene mutation. Polygenic in nature according to models now available. Same genotype may result in different phenotype (pleiotropy) depending on surrounding genes and/or environment.

Environment - Asthma
Allergens hi MW proteins or protein containing molecules. Pollen trees, grass, and weeds Fungal spores Alternaria, etc. Animal dander cats & dogs Household mites/insects ie cockroach

Environment - Asthma
Patterns of Asthmatic Airway Response EAR 10-20 minutes after allergen exposure, resolution in 1-2 hrs. LAR 3-5 hrs and resolution within 6-8 hrs but can last up to 12 hours.

Environment - Asthma
EAR mechanisms Allergen-IgE-mast cell acute mediator release of histamines, prostaglandins, & leukotrienes with subsequent smooth muscle contraction & bronchospasm. Example asthma next.

Early and Late asthmatic response to inhalation of grass pollen

3
FEV1 (liters)

2.5 2 1.5 1 0.5 0

83 0 3 5 7 5 0. 0. 1. 5 9

Diluent Allergen

HOURS

Environment - Asthma
EAR allergen induced prevention Inhaled sodium cromoglycate (SCG) given prior to allergen exposure inhibits both the early and late asthmatic response. Short acting B2 agonists inhibit the early but not late allergen induced response. Anticholinergics variable or no response.

Environment - Asthma
EAR allergen induced prevention. H1 blockers partial inhibition Leukotriene pathway inhibitors modest inhibition of EAR & LAR In-vitro study on human tracheal smooth muscle: complete inhibition of EAR & LAR with H1 blocker, lipoxygenase & cycloxygenase inhibitors.

Environment - Asthma
LAR mechanisms unclear Associated with an influx of inflammatory cells (eos, mast cells, & lymphocytes) after exposure to allergen. This also results in induced airway hyperresponsiveness.

Maintenance of allergen-induced asthma - hypothesis

Allergen + IgE on Mast Cell Allergic Reaction

EAR
Prolonged Airway Hyperresponsiveness Late Asthmatic Response (inflammation occurs here)

Asthma Symptoms on exposure to allergic and Nonallergic stimuli (cold air, smoke, exercise)

Treatment - Asthma
NIH consensus in 1997 with 2002 update. 4 types of asthmatics Sx & Pulmonary Fx Mild Intermittant Step 1 Mild Persistant Step 2 Moderate Persistant Step 3 Severe Persistant Step 4

Treatment Asthma - Goals

1. Minimal or no chronic Sx day or night 2. Minimal or no exacerbations 3. No limitation on activities; no school/work missed. 4. Maintain (near) normal pulmonary fx

Treatment Asthma - Goals

5. Minimal use of short-acting inhaled B2agonist (< 1x per day, < 1 canister/month). 6. Minimal or no adverse effects from medication.

Rx Mild Intermittant Asthma

Sx: day < 2 days/wk or night < 2 nights/mo. Pulm. Fx: > 80% PEF or FEV1; PEFv< 20% Hyperresponsiveness can be normal Rx: No daily medication needed. Rx: Short-acting bronchodilator as needed. Can still get severe asthma exacerbations but often separated by long periods of none.

Rx Mild Persistent Asthma

Sx: day >2/wk but <1x/day or 3-4x mo/noc. Pulm.Fx: >80% PEF/FEV1; PEFv:20-30% Rx: Low Dose IHCS or leukotriene modifier. Rx: Others include Cromolyn, nedocromil, or sustained release theo. (5-15 ug/ml).

Rx Mild Persistent Asthma

Which to use, Montelukast 10 mg once a day or low dose IHCS twice a day? Improvement in pulmonary function
Montelukast about 7.5% within 6 hours IHCS about 15% within 10-14 days

Better Compliance: a pill or IHCS?

Drug-Specific Compliance age 12-17

80 70

Mean % Compliance

60 50 40 30 20 10 0 Theophylline Inhaled Steroid Cromolyn Sodium

Rx Mild Persistent Asthma

LD fluticasone vs Montelukast 10 mg/day 2001 study; FEV1 50-80%, B-agonist only Better morning PEF and FEV1 Less use of rescue albuterol, less nocturnal awakenings, more asthma Sx free days, and less asthma sx scores with fluticasone Retrospective claims data same trends

Rx - Mild Persistent Asthma

Avoid precipitating causes IHCS low dose is best rx Montelukast 10 mg/day second best rx Sustained release theo compounds Cromolyn & Nedocromil consider Also, Rate of Improvement after ICS - Next

Rate of Improvement with ICS

120
% improvement

100 80 60 40 20 0 0 1 2 4 6 12 18 24 Months NIGHT SX FEV1 amPEF No SABA use AHR

Asthma Moderate Persistent

Sx: Daily or > 5x/month at night. Pulm. Fx: >60% - <80% for FEV1 or PEF PEFv: > 30% Rx: Dual therapy with IHCS + Salmeterol or IHCS + montelukast. Which is better?

1 year follow-up dual therapy study (9.2 vs 14.4, p<0.05)

16
% Hospitalized/ED visit

14.4 11.3 9.2

14 12 10 8 6 4 2 0
+S al m et al m et lu ka st ol er er IC S+ s ol

IC S+ m on te

FP

Rx Moderate Persistent Asthma

Several other randomized studies reveal: Better improvement in pulmonary fx and symptom-free days with IHCS+Salmeterol vs IHCS+montelukast. Also IHCS+ salmeterol vs doubling the dose of IHCS only. IHCS + LABA far superior.

Rx Moderate Persistent Asthma

First Line: IHCS (low to med)+LABA 2nd line: IHCS + montelukast 2nd line: Increase IHCS to medium range 2nd or 3rd line: IHCS (low to med) + theophylline (515 ug/ml)

Asthma - Severe Persistent

Sx: Day continual; Night frequent Pulm. Fx: < 60% PEF or FEV1 PEFv: > 30% Tend to be on intermittant oral prednisone Preferred rx: Hi-dose IHCS + LABA

Rx Severe Persistent
Prevent precipitating causes of asthma
1. Allergic Rhinitis
Antihistamines Steroid nasal spray

2. Sinusitis
Antibiotics

Rx Severe Persistent
Prevent precipitating causes of asthma
4. Gastro-esophageal reflux
H2 blocker or proton pump inhibitor

5. Allergen exposure
Avoidance if hx and skin test are compatible.

Rx Severe Persistent
Prevent precipitating causes of asthma 5. Pets evaluate as an asthma trigger 6. Drugs that may exacerbate asthma
NSAID and aspirin B-blockers Ace inhibitors cause cough Illicit drugs especially cocaine

Rx Severe Persistent
Prevent precipitating causes of asthma 7. Does the subject smoke? Get an ABG with carboxyhemoglobin level and if greater than 5% they probably smoke. Urinary cotinine level. Present for 36 hr. 8. Check adherence and inhaler technique. 9. Re-evaluate to make sure dx is correct.

Rx Severe Persistent
Prevent precipitating causes of asthma 10. Get an occupational history related to asthma. 11. Allergy testing. 12. Refer to a specialist.

Asthma Clinic Follow-up

Step down
Every 3-6 months consider reducing therapy if the patient is stable with minimal sx.

Asthma Clinic Follow-up

Step up Indicators of poor asthma control.
awakens at night with sx Recent urgent care visit (ED) Increased need for SABA Uses more than one canistor SABA/month

Before increase check: technique, adherence, recent life change, alternative dx

Asthma Exacerbation (ED)

Rx Initial : If alert, no hypoxemia on pulse oximeter should be albuterol inhalation Q 20 min for one hour with before and after PEF. If after one hour PEF > 70% & comfortable consider D/C with SABA and IHCS or SABA alone. If PEF 50 70%. Systemic CS & SABA. Can admit or D/C depending on overall eval. If PEF < 50% continue Rx, Systemic CS.

Asthma Exacerbation (ED)

Status Asthmaticus a prolonged episode of symptomatic airway obstruction that is poorly responsive to Rx. Admit patient who is hypoxemic, slightly confused, so SOB cannot do initial PEF, cannot get a sustained PEF > 50% of predicted, a pCO2 > 40, or who cannot get good follow-up care and PEF < 70% predicted (ie homeless).

Asthma Exacerbation (ED)

Antibiotics
With or without x-ray

Respiratory Support
When? What type?

Asthma Exacerbation (home)

Action Plan to include
Signs, sx, and PEF How to adjust medication if asthma worse. When to seek medical help. Emergency phone numbers.

Asthma Exacerbation (home)

Incr. wheezing, sx. SABA 2-4 puffs Q-20 min 1 hr or nebulizer Rx & assess at 1 hr. If PEF > 80%, no Sx, & 4h sustained. Then mild exacerbation. Continue prn or if on IHCS double dose for 7-10 days. Contact clinician within 48 hours.

Asthma Exacerbation (home)

Moderate exacerbation. IF after 1 hr PEF 50-80%. Then take 2-4 puffs every 2-4 hrs for 24-48 hrs prn & add oral CS for 3-10 days. At least until sx or PEF stable. Contact clinician with 24 hrs.

Asthma Exacerbation (home)

Severe. PEF < 50% or marked wheezing, SOB, cough, or chest tightness. Or distress is severe (even if PEF > 50%) or response to SABA < 2 hrs. Start oral CS, up to 3 Rx 4-6 puffs every 20 min prn, go to ED. Usually an admission.

Asthma - Vaccinations
Influenza all asthmatics. Asthma exacerbation 28.8% receiving vaccine & 27.7% receiving placebo.
Pneumococcal Vaccine no specific indication. Remember steroid dependent and those with DM.

Asthma Exercised Induced

Stimulated by cold dry air. Swimming best. No LAR. Recover quickly. Max. drop FEV1 is just after exercise. Rx: SABA just before exercise. Montelukast taken the same day, an alternative. Rx: IHCS minimize attacks after 1 mo. but not 1 inhalation before exercise.

Asthma Aspirin Sensitive

Prevalence about 5% of asthmatics or more. Tends to occur in adults with more severe asthma. F/M (2/1). Often steroid dependent. Nasal polyps occur in 50% of ASA. Of all subjects with nasal polyps 20% ASA. Dx: usually by history.

Asthma Aspirin Sensitive

Mechanism (s): 1. ASA and NSAID block the enzyme cyclooxygenase. This may shunt more arachidonic acid to leukotriene synthesis. 2. ASA - more airway cells (eosinophils esp.) with an increase in LTC4 synthase activity & excrete more urinary LTE4 at baseline.

Arachidonic Acid Metabolism

Arachidonic Acid Cyclooxygenase enzyme PGG2 PGD2 PGH2 PGE2 5-lipoxygenase enzyme 5-HPETE LTA4 15-lipoxygenase enzyme

15-HPETE
Lipoxins LTB4

PGF2

TxB2 6-keto PGF1

PGI2

TxA2

LTC4 LTD4

LTE4

Rx Aspirin Sensitive Asthma

Avoid Aspirin and NSAID Use leukotriene modifiying drugs. Aspirin desensitization with maintenance. This also allows use of NSAID. Avoid hydrocortisone succinate (use OH phosphate). Get peculiar allergy.

Asthma CS - Mechanism