asthma And Co-morbid Conditions - World Allergy 1-Lockey.pdf · Asthma and Co-Morbid Conditions...

Asthma and Co-Morbid Conditions

Richard F. Lockey, M.D.

Director, Division of Allergy and Immunology

Department of Internal MedicineUniversity of South Florida College of

MedicineJames A. Haley Veterans’ Hospital

Tampa, Florida

Learning Objectives

• Physicians will gain additional insight about co-morbid conditions associated with asthma.

• Such familiarity will lead to better clinical outcomes and quality-of-life for patients with asthma.

• Treatment guidelines for asthma should address these co-morbid conditions.

1. Food2. Rhinosinusitis

a. Allergicb. Non-allergicc. Infectiousd. Nasal polyposise. Other

3. Gastroesophageal Reflux Disease (GERD)

4. Vocal Cord Dysfunction (VCD)

5. Obesity6. Osteopenia and

Osteoporosis

7. Psychological Problems8. Churg-Strauss Disease9. Sleep Apnea10. Pregnancy11. COPD versus Asthma12. Eczema13. Smoking Cessation14. Infection (Vaccination)15. Bronchiectasis and Cystic

Fibrosis16. Exercise-Induced Asthma17. Others- Endocrine,

Conjunctivitis,Congestive Heart Failure, Pulmonary Embolism, Medications

18. Primary Ciliary Dyskinesia

Introduction• Asthma is perhaps the most treatable of all

chronic diseases.• Continuous treatment necessary to

prevent symptoms and exacerbations. • For optimal outcomes, co-morbid

conditions must be identified and treated.• Co-morbid conditions and their diagnosis

and treatment should be included in asthma guidelines

Questions and procedures for patients with asthma (children and adults)

1. History + ask and think about co-morbid conditions

2. Risk factors for various co-morbid conditions (almost everyone has risk factors)

3. Complete physical examination4. Psychological profile5. Sleep profile6. Weight assessment

Questions and procedures for patients with asthma (children and adults)

7. Smoking (drinking and drug) assessment8. Diet – appropriate calcium and vitamin D.

Exercise (walk 1.5 miles) or stand (1.5 hours)

9. Spirometry and flow volume loop, as necessary

10. Dexa bone scan?11. Rhinoscopy, as indicated12. Vaccinations (flu, Pneumovax, Tdap,

? herpes zoster)13. Others as necessary

Risk factors for exacerbation of difficult-to-treat asthma

39 had 3 severe exacerbations/yr136 subjects

29 had 1 severe exacerbation/yr

Brinke , et al. Eur Respir J 2005; 26: 812.

Conclusions

1) Odds ratio (OR) associated with 3 exacerbationsa) severe sinus disease, OR 3.7b) GERD, OR 4.9c) URIs, OR 6.9d) Psychological dysfunction, OR 10.8e) Obstructive sleep apnea, OR 3.4

2) All patients with frequent exacerbations had 1/5 while 52% had 3/5

Brinke , et al. Eur Respir J 2005; 26: 812.

Rhinosinusitis

Rhinosinusitis (Allergic, Nonallergic, Infectious) and AsthmaIncidence and Association

1. Rhinitis (all kinds) linked to sinusitis (rhinosinusitis) and to nasal polyps –all of which are co-morbid conditions of asthma

2. Up to 70% of patients with asthma alsopresent with rhinosinusitis.

Annesi-Maesano I. Allergy 1999;54 (suppl) 7-13

Rhinosinusitis (Allergic, Nonallergic, Infectious) and Asthma

Incidence and Association

3. Allergic rhinitis can be a precursor of asthma

4. Deterioration of rhinitis symptoms negatively impacts bronchial responsiveness and conversely adequate management of rhinitis improves asthma

5. Chronic sinus disease may be linked to severe asthma

Bachert C et al. In: Middleton 7th ed. Allergy: Principles and Practice, p 991

Rhinosinusitis (Allergic, Nonallergic, Infectious) and Asthma

Incidence and Association

6. Postulated that perennial allergic and non-allergic rhinitis rather than seasonal rhinitis predisposes to “sinusitis”

7. Controlling infectious sinusitis may decrease asthma medication needs

Moss MH et al. In: Middleton 6th ed. Allergy: Principles and Practice, 2003, p 1225

Nasal Polyps and Asthma1. Nasal polyps unusual in atopic patients.2. 40 – 80% of aspirin-exacerbated asthma

subjects have nasal polyps and 15% of polyp patients have aspirin-exacerbated asthma.

3. Nasal polyps in 37 – 48% of patients with cystic fibrosis (some patients have concomitant asthma)

4. Bronchial hypersensitivity exists in many patients with polyps.


Gastroesophageal Reflux Disease

(GERD)

Atypical symptoms of GERD

• Chest pain• Hoarseness• Chronic cough• Sore throat• Wheezing

– 80% of subjects with asthma may have GERD

• Throat clearing(feels like “cotton-ball” which cannot clear)

• Globus• Laryngospasm• Dental erosion

-Mujica et al. Postgrad Med 1999-DeVault et al. Am J Gastroenterol 1999

Prevalence of GERD in Children

• Abnormal pH probes common and many such patients have no clinical symptoms

Chiquette et al. J Asthma 2002;39:135Khoshoo et al. Chest 2003;123:1008Sheikh et al. Pediatr Pulmonol 1999;28:181

Effect of GERD Rx on Asthma

• Decreased exacerbations or improved QOL– Littner MR Chest 2005;128:1128

– Sharma B et al. Journal of Gastroenterology2007;13:1706

– Khoshoo V et al. Journal of Pediatric Gastroenterology & Nutrition 2007;44:331

– Shimizu Y et al. Tohoku Journal of Experimental Medicine 2006;209:181

– Jiang SP et al. European Review for Medical & Pharmacological Sciences 2005;9:151

Effect of GERD Rx on Asthma

• Improved PEFR– Kiljander TO et al. Am J Respir Crit Care Med

2006;173:1091

Cochrane Data Base Review of GERD Treatment for Asthma in Adults

and Children (2006)• 12 randomized controlled trials of Rx for GERD in

adults and children• 2 independent reviewers• Interventions included proton pump inhibitors (6), H2

receptor antagonists (5), surgery and conservative management (1)

• Temporal relationship in 4 trials found between asthma and GERD

• Anti-reflux Rx did not consistently improve lung function, asthma symptoms, nocturnal asthma and medication use

• Conclusion: No overall improvement but subgroups may gain benefit; albuterol use may be decreased

GERD and Chronic Rhinosinusitis

• Upper respiratory symptoms frequent among subjects with symptomatic GERD Dx’d by esophageal study

• GERD associated with chronic rhinosinusitis in children and adults

-Theodoropoulos DS et al. Am J Resp Crit Care Med 2001;164:72-6-Barbero GJ. Otolaryngol Clin North Am 1996;29:27-38-Phipps CD et al. Arch Otolaryngol Head Neck Surg 2000;126:831-6-Ulualp SO et al. Am J Rhinol 199;13:197-202-DiBaise et al. Ann Int Med 1998;1291078-83

Vocal Cord Dysfunction (VCD)

Vocal Cord Dysfunction (VCD)Definition of VCD• Paradoxical adduction (closure) of the vocal

cords/ folds during inspiration and/or early expiration

• “Irritable larynx syndrome”• Episodic laryngeal dysfunction triggered by

irritant exposures or can occur spontaneously with variable clinical manifestations: chronic cough, frequent throat-clearing, globus pharyngeus, choking episodes, dysphonia, masquarades as asthma; exercise–induced asthma, or complicates asthma

-Mikita JA, et al., All Asthma Proc 2006;27:411.-Bahrainwala AH, et al., Curr Opin Pulm Med 2001;7:8.-Byrd RP, et al., Postgrad Med 2000;108:37.-Balkissoon R, In: Nonallergic Rhinitis, Baraniuk JN, Shusterman D (eds): Informa

Healthcare USA, Inc., New York, pp. 411, 2007.

VCD

Diagnostic Criteria1) Paradoxical inspiratory

adduction of anterior 2/3 vocal folds on laryngoscopy

2) ± Posterior diamond-shaped glottic gap

3) Variable extrathoracic obstruction on flow volume loops

posteriorposterior

anterioranterior

Spirometry and Flow Loop• FEV1 (88% of predicted),

no bronchodilator response.

Flattened inspiratory loop

Vocal Cord Dysfunction (VCD)

National Jewish Health95 subjects with asthma and/or VCDa. 42 had VCD aloneb. 53 had VCD with asthmac. 28% had been intubatedd. Misdiagnosed with asthma for average

of 4.8 yrse. “Very sick patients” with VCD

Newman AB et al. Am J Resp Crit Care Med 1995;152:1382

VCD: Treatment

• Multidisciplinary approach

• Treat underlying disorders; rhinitis, GERD/LPR, asthma

• Suppress cough: cough causes laryngeal injury• Speech pathology: throat relaxation, cough

suppression, throat clearing suppression, instruct on control of laryngeal responses to irritants and how to abort an acute attack

• Discontinue unnecessary medication

• Psychological support

Obesity

Asthma and ObesityObesity Increases the Incidence of Asthma• 17 prospective studies, 9 in adults and 8 in

children• Each involved several thousand subjects• Follow up periods of 2-21 years• Only 1 failed to show an increased

incidence of asthma in the obese• Obesity antedates asthma• Many controlled for exercise• Most show an effect of overweight as well

Asthma and Obesity Obesity and Asthma Control

Obesity Reduces Obesity Doesn’t ReduceAsthma Control Asthma Control

St. Pierre et al. (2006) Kwong et al (2006)*Dixon et al. (2006)Lavoie et al. (2006)Peters-Golden et al. (2006)Lessard et al. (2008)**Mosen et al. (2008)Vogt et al. (2008)Boulet et al (2007)

* Only study performed in children** Reduced control occurred despite similar ability to perceive

symptoms

Asthma and ObesityObesity Increases Asthma Severity

• 3095 patients in the National Asthma Survey• “Compared to non-overweight subjects, obese

subjects were significantly more likely to.”

Odds RatioReport continuous symptoms 1.66Miss work 1.35

Use short acting β2 agonists 1.36Use inhaled steroids 1.34

Have severe persistent asthma 1.42(GINA class IV)

Taylor et al. Thorax, Jan 2008

Osteoporosis and Osteopenia

Osteoporosis and OsteopeniaInhaled Corticosteroid (ICS) Use and Bone

Mineral Density• One in three asthmatics in UK receive ICS

(majority beclomethasone in current study)– Approximately 30% receive more than 800

micrograms per day

• 2000 micrograms per day for 7 years or 1000 micrograms per day for 14 years would result in a decrease of 1 SD in bone mineral density (double the risk of fracture)

LancetLancet 2000;335:13992000;335:1399--403403

Osteoporosis and Osteopenia

Stratify Risk of Osteoporosis• High risk

– Chronic systemic corticosteroid (CS) (daily or qod)

– Systemic CS > 4 weeks continuously– Systemic CS bursts > 4 per 12 months– >2 other risk factors with chronic, moderate to

high dose inhaled corticosteroid

Ledford D et al. J Allergy Clin Immunol 1998;102(3):353-62

Psychosocial Problems


• Stress is linked to many diseases –asthma is no exception

• Stress may alter immune system in direction of Th2 response

• Depression particularly dangerous –especially for severe asthma

• Psychological problems are particularly dangerous for a patient with severe asthmaBloomberg GR, Chen E. Immunol Allergy Clin N Am 2005;25,83


• Stress associated with increased prevalence of asthma

• Stress associated with increased exacerbations

• ? whether asthmatic children have significantly more total anxiety disorders, lower self-esteem, greater functional impairment, past school problems, past psychiatric illnesses, and familial stress

-Guilbert T et al. In Middleton 7th ed. Allergy: Principles and Practice, 2009, pp 1319-1343-Wright RJ et al. Am J Respir Crit Care Med 2002;165:358-365-Sandberg S et al. Lancet 2000;356:982-987

Psychosocial ProblemsTreatment• Compliance is always a problem in

treatment, particularly those with psychological problems

• Compliance is always a suspected problem in patients with severe asthma

• Treat with prevention education, counseling, support, access to care and appropriate medications

- Guilbert T et al. In Middleton 7th ed. Allergy: Principles and Practice, 2009, p1333-National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines forthe diagnosis and management of asthma: clinical practice Guidelines. Bethesda (MD): NIH/National Heart, Lung, and Blood Institute 2007; August:4051

Asthma and Sleep Apnea


Definition

Obstructive Sleep Apnea Syndrome (OSAS) is:1. Complete or partial collapse of the

upper airways during sleep with consequent cessation of breathing despite ongoing respiratory effort plus coexistent daytime somnolence.

2. Coexistent daytime somnolence (disabling)

-Staevska MP, Baraniuk JN. Rhinitis and Sleep Apnea. In: Baraniuk J, -Shusterman D (eds). Nonallergic Rhinitis, 2007, Informa Healthcare, New York,449-472


Adult Symptoms

At least one of the following 3 observations:1. Patient complaints of unintentional sleep

episodes during wakefulness, daytime sleepiness, unrefreshing sleep, fatigue, or insomnia.

2. Patient wakes up at night with breath holding, gasping, or choking.

3. Bed partner observes symptoms of loud snoring and/or breathing interruptions.

-Staevska MP, Baraniuk JN. Rhinitis and Sleep Apnea. In: Baraniuk J, -Shusterman D (eds). Nonallergic Rhinitis, 2007, Informa Healthcare, New York,449-472

Asthma and Sleep ApneaSymptoms - Children1. The caregiver reports snoring and/or labored or

obstructed breathing during sleep.

2. The caregiver observes at least one of the following: - Paradoxical inward rib cage motion during

inspiration movement arousals- Diaphoresis- Neck hyperextension during sleep- Excessive daytime sleepiness, hyperactivity, or

aggressive behavior- Slow rate of growth- Morning headaches- Secondary enuresis

Staevska MP, Baraniuk JN. Rhinitis and Sleep Apnea. In: Baraniuk J, Shusterman D (eds). Nonallergic Rhinitis, 2007, Informa Healthcare, New York, 449-472

Conclusions

• HS a problem in primary school children• HS associated with significant risk factors• HS associated with sleep-disorder

breathing symptoms• HS associated with sleep-disordered

breathing symptoms and adverse neurobehavioral outcomes

HS = habitual snoring

Li AM, et al. Chest 2010;138(3):519-527

Asthma and Sleep ApneaPrevalence of Obstructive Sleep

Apnea-Hypopnea (OSAH) in Severe versus Moderate Asthma

1. 23 of 26 (88%) with severe asthma, 15 of 26 (58%) with moderate asthma, 8 of 26 (31%) controls without asthma had apnea-hypopnea index ≥ 15 events/hour.

Using more restrictive criteria, 50% severe, 23% moderate, and 12% (control) of subjects had obstructive sleep apnea (OSA).

2. No correlation between severity of sleep-disordered breathing and asthma severity.

Julien JY et al. J Allergy Clin Immunol 2009;124:371-6


1. Risk of sleep apnea increases with nasal obstruction, large adenoids and tonsils, and elongated face.

2. Rhinitis appears to increase the risk of obstructive sleep apnea.

3. Many other risk factors associated with sleep apnea include obesity, gastroesophageal reflux, endocrine problems, and others.


Treatment1. Recognition: look for signs and

symptoms. (Epworth Sleepiness Scale)2. Treat underlying disorders from upper

airway disease to obesity.3. Continuous Positive Airway Pressure

(CPAP)

Pregnancy

Pregnancy

Effect of Pregnancy on Asthma• Meta-analysis shows that one-third

improve, one-third stay the same, and one-third deteriorate.

• URIs the most common precipitants of severe asthma during pregnancy.

-Juniper EF, Newhouse MT. Effect of pregnancy on asthma: a systemic reviewand meta-analysis. In: Schatz M, Zeiger RS, Claman H, eds. Asthma andImmunologic diseases in pregnancy and early infancy. New York, Marcel Dekker; 1998:401

-Murphy VE et al. Obster Gynecol 2005;106:1046-1054

COPD versus Asthma

Asthma and COPD: Challenging the Assumptions – Evidence for a Disease Continuum

Asthma COPD Evidence

May be smokers

Usually smokersUp to 25% of cases of COPD present in nonsmokers (Behrendt. Chest 2005;128:1239)

Reversible airway obstruction

Nonreversible airway obstruction

Almost half of adults with moderate to severe childhood asthma have irreversible airway obstruction (Limb et al. J Allergy Clin Immunol 2005;116:1213

Gulliver T et al. CHEST Physician September 2008, p 9

Asthma and COPD: Challenging the Assumptions – Evidence for a Disease Continuum

Asthma COPD Evidence

Eosinophilic inflammation

Neutrophilic inflammation

Eosinophilia in mild COPD exacerbations; neutrophilia present in COPD and asthma exacerbations (Qiu et al. Thorax 2007;62:475)

Bronchitis symptoms uncommon

Bronchitis common

Asthmatics at high risk for acquiring symptoms of chronic bronchitis (Silva et al. Chest 2004;126:59)

Gulliver T et al. Chest Physician September 2008, p 9

Smoking Cessation

Smoking Cessation and Asthma

• Active smoking and exposure to second-hand smoke trigger and aggravate asthma

• Studies link smoking with more frequent attacks, more severe symptoms, increased hospitalization rates, and declined lung function

Gritz ER et al. Gritz ER et al. Am J Prev Med 207;33(6S):S414Am J Prev Med 207;33(6S):S414--S422S422

Asthma and Infection (Vaccination)

Influenza Vaccine• An injectable trivalent, inactivated viral vaccine (TIV)

composed of seasonal H3N2, H1N1, and Influenza B• A live attenuated vaccine (LIAV) is also available• Studies show no increase in symptoms after

vaccination• Low to medium dose ICS does not affect vaccine

responsiveness– High dose ICS does decrease response to

Influenza B• Current evidence is conflicting on the effectiveness

of influenza vaccination in preventing morbidity and mortality in COPD and asthma

• Influenza vaccination is recommended in asthmatics and COPD based upon the known complications of influenza infection

CDC. MMWR: Recommendations and Reports 2009;58:1-52 (RR-8)

Streptococcus pneumoniae

• The risk of pneumonia is 11% to 17% in two studies of asthma.

• The Advisory Committee on Immunization Practices (ACIP) recommends all adults with asthma(19-64 yrs) receive the vaccine for S. pneumoniae (PPV-23).

--Talbot T et al. Talbot T et al. N Engl J Med N Engl J Med 2005;352:20822005;352:2082--9090--Juhn YJ et al. Juhn YJ et al. J Allergy Clin Immunol J Allergy Clin Immunol 2008;122:7192008;122:719--2323--Jung J et al. Jung J et al. J Allergy Clin Immunol J Allergy Clin Immunol 2010;125;2172010;125;217--2121

Pertussis

• 5,000-7,000 cases occur each year in the U.S. • Adults can serve as a reservoir for infection of

children due to waning immunity• Infection with B. pertussis can lead to

exacerbations of both asthma and COPD• A combination vaccine of tetanus, diphtheria,

and pertussis [Adacel (TdaP)] is recommended in these patients as a single dose vaccination for adults age 19-64– Vaccination has been shown to reduce the number of

cases by 44%

CDC. CDC. MMWR: Recommendations and Reports 1997;46:1-25(RR-7)CDC. MMWR: Recommendations and Reports 2006;55:1-37 (RR-17)

Herpes Zoster• Reactivation of Varicella Zoster leads to

significant morbidity in aging adults, and patients on high dose inhalational or oral steroids (>20mg/day prednisone) may be at higher risk.

• Zostavax has been shown to reduce the incidence of herpes zoster reactivation by 51.3% and post-herpetic neuralgia by 66.5%.

• Recommended for all adults (60 and older) as a single dose. Also recommended for all asthmatics and patients with COPD, 60 years and older if on >20mg/day of prednisone (or equivalent glucocorticosteroid).

CDC. MMWR: Recommendations and Reports 2008;57:1-30 (RR-5)

Bronchiectasis and Cystic Fibrosis


1. Bronchiectasis can be associated asthma, especially severe asthma. High resolution CT (HRCT) scans of severe asthmatics indicate bronchiectasis present in 40%.Many children with bronchiectasis confirmed by HRCT have asthma; spirometry does not necessarily correlate with the severity of symptoms.

-Gupta S et al. Chest 2009;136:152-Santamaria F et al. Chest 2006;130:480


2. Allergic bronchopulmonary aspergillosis has been estimated to occur in 1 to 2% of patients with chronic asthma and 1 to 50% of patients with cystic fibrosis.

3. Patients with cystic fibrosis can also have asthma which responds to asthma therapy.

-Vlahakis NE et al. Mayo Clin Proc 2001;76:930-Stevens DA et al. Clin Infect Dis 2003;37(suppl 3):s225

Asthma in Cystic Fibrosis

• Epidemiologic study of cystic fibrosis 1995

• 3,976 of 12,622 CF children and adults or 31% were receiving asthma treatment

Balfour-Lynn IM. J R Soc Med 2003;96(Suppl 43):30-34

Treat Co-Morbid Conditions and Reduce Asthma Morbidity and Mortality

1. How goes the nose, so goes the chest; Rx nasal disease, especially polyps

2. GERD in and of itself can be a severe and life-threatening as well as decrease quality of life. GERD can exacerbate asthma and asthma can exacerbate GERD. Rx appropriately.

3. Treat VCD or concomitant VCD.4. Overweight subjects refer to Weight

Watchers; encourage weight reduction.


5. Give calcium and vitamin D and encourage exercise for all patients. Look for and, where appropriate, decrease risk factors.

6. Psychiatric care, as necessary, as with any other disease.

7. Suspect, diagnose, and treat sleep apnea.

8. Give 24 hour access to all patients with asthma, particularly pregnant subjects.


9. Asthma and COPD can become the same disease.

10. Assist in smoking cessation.11. Bronchiectasis must be suspected in

severe asthma. So too, should other diseases such as ABPA, CF, etc.

Know when to refer for help, especially with co-morbid conditions.

Conclusions• Asthma is perhaps the most treatable of all

chronic diseases.It should be treated continuously to prevent symptoms and exacerbations.

• For optimal outcomes, co-morbid conditions must be identified and treated.

• Co-morbid conditions and their diagnosis and treatment should be included in asthma guidelines

Thank you!

Risk Factors for Fatal Asthma>> Asthma history

- Previous severe exacerbation (e.g., intubation or intensive care unit (ICU) admission for asthma)- Two or more asthma hospitalizations for asthma in the past year - Three or more emergency department (ED) visits for asthma in the past year- Hospitalization or ED visit for asthma in the past month

-Adapted from NIH/NHLBI National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma: Clinical practice guidelines. Bethesda (MD): 2007-Guilbert T et al. In Middleton 7th ed. Allergy: Principles and Practice, 2009, p 1323

Risk Factors for Fatal Asthma>> Asthma history

- Use of > 2 canisters per month of short-acting bronchodilators (SABA)- Difficulty perceiving asthma symptoms or severity of exacerbations- Other risk factors: lack of a written asthma action plan, sensitivity to Alternaria



Risk Factors for Fatal Asthma

CT Scan of a Patient with Chronic Sinusitis: Opacification of the Ostiomeatal Complex and the

Maxillary Sinus is seen Bilaterally


Mass Psychogenic Illness Presenting as Acute Stridor in an Adolescent Female Cohort

• 14 subjects, 12 evaluated, all with inspiratory stridor over 10 months

• 14 to 18 yrs (9th to 12th grade)• School dance team• Polyurethane and paint temporally

involved in some but sentinel case presented before exposure

Powell SA, Nguyen CT, Gaziano J, Lewis V, Lockey RF, Padhya TA. Ann Otol Rhinol Laryngol 2007;116:525-531

Breakdown of Additional Symptoms EncounteredPatients

Symptom No. %

Breathing difficulty 13 92.9

Breathing difficulty with physical activity 12 85.7

Chest Discomfort or pain 11 78.6

Headache 11 78.6

Dizziness 8 57.1

Numbness 6 42.9

Muscle aches 6 42.9

Anxiety 6 42.9

Cough 6 42.9

Chills 5 35.7

Nausea 4 28.6

Rhinitis 3 21.4

Lethargy 3 21.4

Excessive sweating 1 7.1

Neck stiffness 1 7.1Powell SA, Nguyen CT, Gaziano J, Lewis V, Lockey RF, Padhya TA. Ann Otol Rhinol Laryngol 2007;116:525-531

Mass Psychogenic Illness Presenting as Acute Stridor in an Adolescent Female Cohort

• 14 subjects, 12 evaluated, all with inspiratory stridor over 10 months

• 14 to 18 yrs (9th to 12th grade)• School dance team• Polyurethane and paint temporally

involved in some but sentinel case presented before exposure

Powell SA, Nguyen CT, Gaziano J, Lewis V, Lockey RF, Padhya TA. Ann Otol Rhinol Laryngol 2007;116:525-531

Breakdown of Additional Symptoms EncounteredPatients

Symptom No. %

Breathing difficulty 13 92.9

Breathing difficulty with physical activity 12 85.7

Chest Discomfort or pain 11 78.6

Headache 11 78.6

Dizziness 8 57.1

Numbness 6 42.9

Muscle aches 6 42.9

Anxiety 6 42.9

Cough 6 42.9

Chills 5 35.7

Nausea 4 28.6

Rhinitis 3 21.4

Lethargy 3 21.4

Excessive sweating 1 7.1

Neck stiffness 1 7.1Powell SA, Nguyen CT, Gaziano J, Lewis V, Lockey RF, Padhya TA. Ann Otol Rhinol Laryngol 2007;116:525-531

Causes of increased exposure of the esophagus to gastric refluxate

• Ineffective peristalsis

• Reduced salivary secretion

• Reduced secretion from esophageal submucosal glands

Defective esophageal clearance

• Inappropriate and prolonged transient relaxations

• Reduction in basal LES pressure/tone

LES ‘dysfunction’

• May trap a reservoir of gastric contents above the diaphragm, increasing reflux

• May compromise LES function

Hiatal hernia

• Pregnancy• Obesity• Bending• Straining• Coughing• Tight clothes

Increased intra-abdominal pressure

• May result in an increase in the volume of gastric contents available for reflux into the esophagus

• Exact role in GERD remains to be clarified

Delayed gastric emptying

Medications that may aggravate GERD symptoms by impairing LES

function• β-adrenergic

agonists• Theophylline• Anticholinergics• Tricyclic

antidepressants

• Progesterone

• α-adrenergic antagonists

• Diazepam• Calcium channel

blockers

Medications that may aggravate GERD symptoms by damaging the

esophageal mucosa• Tetracycline• Quinidine• Potassium chloride tablets• Iron salts• Aspirin and other NSAIDs• Bisphosphonates

Johnsson et al. Gullet 1992

Symptom patterns in GERD

• Reflux-related symptoms occur predominantly after meals

• Reflux-related symptoms are often triggered by– unusually large meals– fatty, spicy, or acidic foods– bending, stooping, or lying down– lifting, straining, or other strenuous activities

• The frequency of reflux-related symptoms varies widely

24.4%

>1/ week

Oliveria et al. Arch Intern Med 1999

0

5

10

15

20

25

30

21.5%

Daily

16.5%

>1/month

11.5%

1/month

13.8%

<1/month

Frequency of heartburn

% r

espo

nden

tsFrequency of heartburn

11.3%

1/week

• Esophageal– Barrett’s

esophagus– adenocarcinom

a

– stricture– ulceration

– bleeding

• Extra-esophageal– asthma

– reflux laryngitis– vocal cord

ulcers

– subglottic stenosis

– tracheal stenosis

Complications of GERD

Management

Medical Management of GERD• Oral antacids & alginates: minimally

effective• H2 blockers in divided doses: moderately

effective• PPIs once or twice daily: moderately to

highly effective– Some risk of bacterial overgrowth, decreased

absorption of B12, iron and calcium– Long term Rx necessary, usually 3-6 months

and often longer and often twice daily

• Prokinetic agents: questionably effective

Surgical Therapy for GERD1. Antireflux surgery, performed by an

experienced surgeon, is a maintenance

option for patients with documented GERD.a. Two published studies show

surgery more effective than medical

therapy. (One study compared antacids and lifestyle changes over 36-months. Second study compared surgery

versus


experienced surgeon, is a maintenance option for patients with documented GERD.b. Randomized trial 310 patients

initially controlled with omeprazole40 mg per day found surgery to be slightly superior (maintenance of esophagitis healing and symptoms) to omeprazole 20 mg per day at the end of 3 yr period.

Lundell L et al. Gastroenterology 1998;114:A207


experienced surgeon, is a maintenance

option for patients with documented GERD.c. If dose is titrated to 40-60 mg

perday of omeprazole medical and surgical treatments equal.

Additional Studies NeededThe American Lung Association Asthma Clinical Research Centers study entitled “Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma: A Randomized Controlled Trial” is under consideration for submission for publication. The Division at the University of South Florida is one of the 19 research centers for the study.

Snoring in Primary School Children

• Validated questionnaire completed by parents to assess sleep and day-time behaviors of Chinese children, 5-14 yrs

Li AM, et al. Chest 2010;138(3):519-527

• 6,349 / 9,172 questionnaires returned

• Habitual snoring (HS) 7.2%

• Male OR 2.5 (1.7-3.6), BMI z score OR 1.4 (1.1-1.6), maternal HS OR 3.4 (2.0-5.7), paternal HS OR 3.8 (2.7-5.5), allergic rhinitis OR 2.9 (2.0-4.2), asthma OR 2.4 (1.2-5.2), nasosinusitis OR 4.0 (1.5-10.6), tonsillitis OR 3.1 (1.9-5.1) in past 12 months independent risk factors associated with HS

Li AM, et al. Chest 2010;138(3):519-527

Results

Results (cont’d)

• HS associated with daytime, nocturnal, parasomniac, and sleep-related breathing symptoms

• Independent risk factor for parent-reported poor temper 1.9 (1.4-2.5), hyperactivity 1.7 (1.2-2.5), and poor school performance 1.7 (1.2-2.5)

Li AM, et al. Chest 2010;138(3):519-527

Do Inhaled Steroids Increase the Risk of Osteoporosis?

• Evidence-based answer:1) Conventional doses for asthma are not

associated with significant bone loss at 2 to 3 years follow-up (strength of recommendation: A

2) Higher doses may be associated with negative bone density changes in up to 4 years: C

3) Evidence lacking on whether nasal steroids increase risk.

4) Longer-term studies are necessaryGerayli F, Loven B. Gerayli F, Loven B. J Fam PractJ Fam Pract 2007;56:1312007;56:131--136136

Recommendations

• Encourage weight-bearing and aerobic exercise to all patients with asthma

Gerayli F, Loven B. J Fam Pract 2007;56:131-136

Osteoporosis Risk Factors

Kearney DM, Lockey RF. Kearney DM, Lockey RF. Ann Allergy Asthma ImmunolAnn Allergy Asthma Immunol 2006;96:7692006;96:769--776776

Not modifiable Potentially modifiable

Female sex Oral corticosteriod use

Advanced age Low body weight (<60 kg)

White race Sedentary lifestyle

History of previous fracture as an adult

Excessive caffeine intake

Estrogen deficiency or oophorectomy before the age of 45 years

Smoking

Osteoporosis Risk Factors*Osteoporosis Risk Factors*


*Adapted from National Institutes of Health Consensus Developmen*Adapted from National Institutes of Health Consensus Development Panel on t Panel on Osteo porosis Prevention, Diagnosis, and Therapy, TangsinmankongOsteo porosis Prevention, Diagnosis, and Therapy, Tangsinmankong et al, et al, Maricic, and Campion and MaricicMaricic, and Campion and Maricic


Orchiectomy or testosterone deficiency

Heavy alcohol use

Family history of osteoporosis Lifelong low calcium or vitamin D intake

History of nontraumatic fracture in first-degree relative

Lactose intolerance or milk allergy

Osteoporosis Risk Factors* Osteoporosis Risk Factors* (cont(cont’’d)d)

*Adapted from National Institutes of Health Consensus Developmen*Adapted from National Institutes of Health Consensus Development Panel on t Panel on Osteoporosis Prevention, Diagnosis, and Therapy, TangsinmankOsteoporosis Prevention, Diagnosis, and Therapy, Tangsinmankong et al, Maricic, ong et al, Maricic, and Campion and Maricicand Campion and Maricic



Endocrine disease: diabetes mellitus, Cushing syndrome, Addison disease, hyperthyroidism, hyperparathyroidism

Certain antiepileptics and anticoagulants, other medications*†

Hematologic disease: multiple myeloma, mastocytosis, pernicious anemia

Lifelong low calcium or vitamin D intake

Malabsorption syndromes

Osteoporosis Risk Factors* Osteoporosis Risk Factors* (cont(cont’’d)d)

**Adapted from National Institutes of Health Consensus DevelopmentAdapted from National Institutes of Health Consensus Development Panel on Osteoporosis Prevention,Panel on Osteoporosis Prevention,Diagnosis, and Therapy, Tangsinmankong et al, Maricic, and CaDiagnosis, and Therapy, Tangsinmankong et al, Maricic, and Campion and Maricicmpion and Maricic

†† Includes pehytoin, heparin, warfarin, cyclosporine, methotexate Includes pehytoin, heparin, warfarin, cyclosporine, methotexate , and excessive thyroid hormone , and excessive thyroid hormone replacementreplacement


Medications for the Prevention and Treatment of Osteoporosis

Kearney DM, Lockey RF. Ann Allergy Asthma Immunol 2006;96:769-776

Medications for the Prevention and Treatment of Osteoporosis

Medication Recommended dosage

Major adverse effects

Calcium 1,000 to 1,500 mg orally divided 2 to 3 times a day

Hypercalcemia, constipation, renal calculi

Vitamin D 400 to 800 IU orally a day

Hypercalcemia, nausea, renal calculi

Hormonal therapy: conjugated equine estrogen

0.625 mg orally once a day

Increased risk of pulmonary emboli, myocardial infarction, strokes, breast cancer


Medications for the Prevention and Treatment of Osteoporosis (cont’d)



Bisphosphonates: ibandronate (Boniva), risedronate (Actonel), alendronate (Fosamax)

150 mg once a month, 35 mg orally once a week, 35-70 mg orally once a week

Esophageal ulcers, dyspepsia, acid reflux, esophagitis, timing and positional requirements





Calcitonin 200 IU intra-nasally once a day or 100 U subcutaneously or intramuscularly every other day

Bronchospasm, nasal symptoms, osteogenic sarcoma with intramuscular or subcutaneous dosing





Selective estrogen receptor modulators: raloxifene (Evista)

60 mg orally once a day

Pulmonary embolism, retinal vein thrombosis, hot flashes, depression

Anabolic medications: teriparatide (Forteo)

20-40 µg subcutaneously once a day

Symptomatic orthostatic hypotension, mild intermittent hypercalcemia, hyperuricemia


Asthma in Cystic FibrosisUse of pulmonary therapies reported to North American Epidemiologic Study of Cystic Fibrosis in 1995 (12,622 CF children and adults) related to the presence of concomitant asthma (reported in 31.5% of the patients)

Asthma No asthma(%) n=3976 (%) n=8646

Oral bronchodilators 27 12

Inhaled bronchodilators 95 76Oral corticosteroids 31 21Inhaled corticosteroids 45 17

Cromlyn/nedocromil 48 11BalfourBalfour--Lynn IM. Lynn IM. J R Soc MedJ R Soc Med 2003;96(Suppl 43):302003;96(Suppl 43):30--3434

Factors that Support Diagnosis of Cystic Fibrosis Asthma

• History of recurrent wheezing• Positive family history atopy in first degree

relative• Patient has history of atopy (eczema, hay

fever, food allergy)• Positive skin prick tests or serum

radioallergosorbent tests to aeroallergens (excluding Aspergillus)

BalfourBalfour--Lynn IM. Lynn IM. J R Soc MedJ R Soc Med 2003;96(Suppl 43):302003;96(Suppl 43):30--3434

Factors that Support Diagnosis of Cystic Fibrosis Asthma (cont’d)

• High serum IgE (excluding ABPA)• Physiology supportive (spirometry,

bronchodilator responsiveness, BHR)• Other diagnoses excluded (gastro-

oesophageal reflux, malacic airways, ABPA obliterative bronchiolitis)

• Response to anti-asthma medication

BalfourBalfour--Lynn IM. Lynn IM. J R Soc MedJ R Soc Med 2003;96(Suppl 43):302003;96(Suppl 43):30--3434

King P. King P. DrugsDrugs 2007:67(7):9652007:67(7):965--974974

Study (year) No. of pts

Study design Therapy (daily dose) and duration

Findings

ICS

Elborn et al. (1992)

20 Randomised, double-blind, crossover, placebo-controlled

Beclametasome (1500µg) 6 weeks

↓ Daily sputum, minor changes in PEFR and FEV1

Tsang et al.(1998)

24 Randomised, double-blind, placebo-controlled

Fluticasone propionate (500µg)

↓ Sputum markers (IL-1, IL-8, LTB4)

Summary of Clinical Trials of ICS and Macrolides Summary of Clinical Trials of ICS and Macrolides in Bronchiectasisin Bronchiectasis

DDLCOLCO = pulmonary diffusion capacity for carbon monoxide;= pulmonary diffusion capacity for carbon monoxide; FEVFEV11 = forced expiratory = forced expiratory volume in 1 second; volume in 1 second; FVCFVC = forced vital capacity; = forced vital capacity; ICSICS = inhaled corticosteroids; = inhaled corticosteroids; ILIL = = interleukin; interleukin; LTLT = leukotriene; = leukotriene; PEFRPEFR = peak expiratory flow rate; pts = patients; = peak expiratory flow rate; pts = patients; ↑↑ indicates increased; indicates increased; ↓↓ indicates decreased indicates decreased King P. King P. DrugsDrugs 2007;67(7):9652007;67(7):965--974974



Findings

ICS

Tsang et al.2005


Fluticasone propionate (1000µg)52 weeks

↓ Sputum volume in subgroups

Martinez-Garcia et al.2006

86 Randomised Fluticasone propionate (500 and 1000µg)6 months

↓ Sputum volume and cough, ↑quality of life


King P. King P. DrugsDrugs 2007;67(7):9652007;67(7):965--974974



Findings

Macrolides

Koh et al.1997


Roxithromycin (8 mg/kg)12 weeks

↓ Airway reactivity (methacholine challenge)

Tsang et al.1999


Erythromycin (1000mg)8 weeks

↑ FEV1 and FVC, ↓sputum volume





Findings

Macrolides

Davies and Wilson2004

39 Prospective study

Azithromycin (dose varied)4 months

↓ Symptoms and sputum, ↑ spirometry (DLCO)

Cymbaala et al.2005

11 Randomised, open-label, crossover

Azithromycin (1000mg)6 months

↓ Sputum volume

Yalcin et al.2006

34 Randomised, placebo-controlled

Clarithromycin (15 mg/kg)3 months

↓ Sputum volume, ↓sputum markers



Smoking Cessation and Asthma (cont’d)

• Secondhand smoke associated with increased symptoms, poor quality of life, reduced lung function, increased hospitalizations and emergency visits

• Effectiveness of treatment of asthma may be compromised by smoking

Gritz ER et al. Gritz ER et al. Am J Prev Med 207;33(6S):S414Am J Prev Med 207;33(6S):S414--S422S422

Asthma and Smoking

• Smoking asthmatics have increased numbers of neutrophils

• Increased levels of IL-8• Decreased numbers of eosinophils in

sputum • Smoking may shift the inflammatory

phenotype from eosinophilia towards neutrophilia

• Smoking may increase steroid-resistance in asthma

Hylkema MN. Hylkema MN. Eur Respir JEur Respir J 2007;29(3):4382007;29(3):438--445 445

Tolia V, Vandenplas Y.. Aliment Pharmacol Ther 2009;29(3):258Tolia V, Vandenplas Y.. Aliment Pharmacol Ther 2009;29(3):258––272272

Symptom Reference Population Size

Definition of extra-oesophageal symptom

Prevalence of extra-oesophageal symptom in children with GERD

Asthma 13.2% vs. 6.8% of controls (P < 0.0001)

Respiratorysymptoms

Pneumonia El-Serag et al.

1980 with GERD + 7980 controls

Physician diagnosis

6.3% vs. 2.3% of controls (P < 0.0001)

Bronchiectasis 1% vs. 0.1% of controls (P < 0.0001)

Prevalence of ExtraPrevalence of Extra--Oesophageal Symptoms in Children with GERDOesophageal Symptoms in Children with GERD

ALTEALTE, apparent life, apparent life--threatening event; threatening event; ENTENT, ear, nose and throat; , ear, nose and throat; GERDGERD, gastro, gastro--oesophageal reflux disease; oesophageal reflux disease; RIRI, reflux index (% of total time when pH < 4); , reflux index (% of total time when pH < 4); WHOWHO, , World Health OrganizationWorld Health OrganizationAdapted from Tolia V. Adapted from Tolia V. Aliment Pharmacol TherAliment Pharmacol Ther 2009;29(3):2582009;29(3):258--272272




ALTE

Tolia173 withGERD + Physician

20% vs. 31% of controls (P < 0.12)

Respiratorysymptoms

General respiratory symptoms

et al. 169 controls

diagnosis 49% vs. 63% of controls (P < 0.01)

General respiratory symptoms

Khalaf et al. 42 with severe RI + 66 controls

Respiratory distress syndrome defined by clinical features and positive chest radiograph

62% vs. 36% of controls (P = 0.02)


Adapted from Tolia V. Adapted from Tolia V. Aliment Pharmacol TherAliment Pharmacol Ther 2009;29(3):2582009;29(3):258--272272




Sinusitis

El-Serag1980 with GERD + Physician

4.2% vs. 1.4% of controls (P < 0.0001)

ENTsymptoms

Otitis media

et al. 7980 controls

diagnosis 2.1% vs. 4.6% of controls (P < 0.0001)

Dental erosion

Linnett et al. 52 with GERD + 52 healthy controls

WHO criteria for caries

14% had erosion vs. 10% of controls (P < 0.05)






Dental symptoms

Dental erosion

Ersin et al. 38 with GERD + 42 healthy controls

WHO criteria for caries Eccles & Jenkins index for erosion by GERD

76% had erosion vs. 10% of controls (P < 0.0001) 37% had severe erosion vs. 1% of controls (P < 0.05)




continuedcontinued

Symptom Reference Population size Diagnosis of reflux symptom

Prevalence of GERD in patients with extra-oesophageal symptoms

Respiratory symptoms

Asthma Stordal et al.

872 asthmatics + 264 controls

GERD questionnaire

19.7% of asthmatics had a positive GERD symptom score vs. 8.5% of controls (odds ratio, 2.6, P < 0.001)

Prevalance of GERD in Children with ExtraPrevalance of GERD in Children with Extra--Oesophageal SymptomsOesophageal Symptoms

ALTE, apparent lifeALTE, apparent life--threatening event; ATS, American Thoracic Society; ENT, ear, nosthreatening event; ATS, American Thoracic Society; ENT, ear, nose and e and throat, GERD, gastrothroat, GERD, gastro--oesophageal reflux disease; GI, gastrointestinal; GINA, Global Ioesophageal reflux disease; GI, gastrointestinal; GINA, Global Initiative for nitiative for Asthma; ISAAC, International Study of Asthma and Allergies in CAsthma; ISAAC, International Study of Asthma and Allergies in Childhood; NIH, National hildhood; NIH, National Institutes of Health; RI, reflux indexInstitutes of Health; RI, reflux index



Symptom Reference Population size

Diagnosis of reflux symptom



Asthma Barakat et al. 75 asthmatics + 25 controls

Endoscopy / ultrasound

GI symptoms in 65% of those with asthma vs. 16% of controls (P < 0.001)







Asthma Chopra et al. 80 asthmatics + 10 controls

Presence of sciatica tracer in oesophagus in more than two frames

39% of asthmatics demonstrated reflux on scintiscanning vs. 0% of controls (P < 0.05)







Asthma Hughes et al.


Oesophageal pH monitoring; reflux defined as a decrease in pH to < 4 for at least 15 s

Gastro-oesophageal reflux occurred in 33% of asthmatics vs. 57% of controls. No significant difference between the two groups in number or duration of reflux episodes or % of time pH < 4







Asthma Debley et al.


Positivie response to selected questionnaire questions

19.3% of adolescents with current asthma had GERD symptoms vs. 2.5% of adolescents without asthma (P < 0.001)



Symptom Reference Population size Prevalence of GERD in patients with extra-oesophageal symptoms

ENT symptoms

Laryngotracheitis Contencin and Narcy

8 patients consulting for laryngotracheitis + 6 controls

Dual-channel pH monitoring. Pathological gastro-oesophageal reflux defined as RI > 5.2%

62.5% of patients had pathological gastro-oesophageal reflux vs. 16.6% of controls



Reference Pop.size

Study design


Drug and dosage

Outcome

Khoshoo and Haydel

44 Investigator-blinded prospective trial

Asthma ≥ 3 episodes per year despite optimal treatment

Group A: esomeprazole (40 mg/day) / metoclopramide, Group B: ranitidine (150 mg 3 times daily), Group C: control (fundoplication). All had previously had PPI / prokinetic for 1 year

Following 6 months treatment, group B had significantly more exacerbations than groups A and C

Outcomes of GERD Drug Therapy on ExtraOutcomes of GERD Drug Therapy on Extra--Oesophageal SymptomsOesophageal Symptoms


Reference Pop.size

Study design


Drug and dosage

Outcome

Stordal et al.

38 with asthma

Randomized placebo-controlled trial

Physician-diagnosed asthma

Omeprazole 20 mg once daily or placebo for 12 weeks

Asthma symptoms scored by two questionnaires did not differ significantly between groups following treatment

Outcomes of GERD Drug Therapy on ExtraOutcomes of GERD Drug Therapy on Extra--Oesophageal SymptomsOesophageal Symptoms


Inhaled Budesonide in Smokers and Nonsmokers with Mild Persistent Asthma

• Lung function declines in smoking asthmatics quicker than nonsmoking asthmatics

• Benefits of budesonide are similar in both smokers and nonsmokers

O’Byrne PM et al. Chest 2009;136:1514-1520

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