1. Asthma in the elderly
Boonthorn
3 November 2010

2. Outline
• Biology of aging
▫ Immunosenescence
• Epidemiology
• Pathogenesis
• Risk factor
• Special characteristics of asthma in elderly
▫ Asthma VS COPD
• Diagnosis
• Management

3. Biology of aging
• Aging is natural process and not a disease
▫ Aging lung
 aging process may be contributing factor to
deterioration of lung function with progressive age
▫ Proinflammatory condition associated with
dysregulated immune system
▫ Play significant role in pathogenesis of many
chronic inflammatory diseases eg. Alzheimer’s
dementia, cardiovascular disease, type 2 DM
Current Opinion in Pulmonary Medicine 2010, 16:55–

4. Immunosenescence
• changes in the innate and adaptive immune response
associated with increased age
• Increased susceptibility to infection, malignancy and
autoimmunity, decreased response to vaccination, and
impaired wound healing
• facilitate persistence of asthma into late adulthood or
development of asthma after the age of 50 to 60 years
J Allergy Clin Immunol 2010;126:690-9.

5. Age-related changes in innate immunity
Cell type Changes with aging
Epithelial cells Decreased ciliary beat frequency and clearance
Microtubular disarrangements
Dendritic cells Reduced phagocytosis and pinocytosis
Increased IL-6 and TNF-α production
Diminished TLR expression and function
Monocytes/macrophages Reduced phagocytosis
Reduced MHC clas II expression
Reduced cytokine and chemokine secretion
Reduced generation of NO and superoxide
J Allergy Clin Immunol 2010;126:690-9.
Clinical immunology, Principles and Practice.Third edition.

6. Age-related changes in innate immunity
Cell type Changes with aging
Neutrophils Reduced phagocytosis ,bactericidal activity
Reduced chemotaxis
Reduced ROS production
NK cells Increased numbers
Reduced cytotoxicity
Reduced proinflmmatory cytokine and chemokine
production
Reduced proliferative response to IL-2
NKT cells Reduced numbers
Reduced proliferation
Eosinophils Reduced degranulation
Reduced superoxide production
J Allergy Clin Immunol 2010;126:690-9.
Clinical immunology, Principles and Practice.Third edition.

7. Age-related changes in adaptive immunity
Cell type Changes with aging
T cells Reduced Naïve T cell count
Increase memory and effector T cell count
Reduced response and proliferation
Reduced CD28 expression
Accumulation of CD8+CD28+ T cells
Reduced TCR diversity
Reduced signal transduction
B cells Reduced generation of B cell precursors
Increase No. of B1 cells
Reduced BCR diversity
Reduced size and number of GC
Reduced expression of co-stimulatory molecule
Reduced Ab affinity, Isotype switch, Ab specific to foreign Ag
Increase Ab specific to self-Ag
J Allergy Clin Immunol 2010;126:690-9.
Clinical immunology, Principles and Practice.Third edition.

8. Role of immunosenescence on features of asthma.
potential mechanism and clinical effect of immunosenescence on long-
term asthma, late-onset asthma, and asthma exacerbations in the
elderly
J Allergy Clin Immunol 2010;126:690-9.

9. Prevalence of asthma in the US among different age groups.
Data are from the 1999 National Health Interview Study
Drugs & Aging 2000 Nov; 17 (5):385-397.

10. Epidemiology
• In 2004, the US prevalence of asthma for those 65 years
or older was 7%, with 1,088,000 reporting an asthma
attack in the previous 12 months.
• Older asthmatic patients are more likely to be
underdiagnosed, undertreated and hospitalized than
younger
• highest death rate (51.3 per million people) of any age
group .
• Older women are hospitalized more than twice as often
as older men
Current Opinion in Pulmonary Medicine 2010,16:55–59

11. Asthma mortality rates by age, per 1,000,000, age-
adjusted to the 1970 Standard Million
The American Journal of Medicine, Vol 122, No 1, January 2009

12. Phenotype of asthma in the elderly
Respiration 1998;65:347–353

13. Phenotype of asthma in the elderly
Respiration 1998;65:347–353

14. Potential mechanisms for asthma phenotypes in the elderly
long-standing asthma late-onset asthma
Age of onset
(years)
Child or young
adult (<40)
Adult (>40)
Genetic role Likely gene by environment Likely epigenetic, including oxidative
stress and shortened telomeres
Infection Viral – rhinovirus and RSV Viral – RSV, influenza and bacterial
(e.g. Chlamydia pneumoniae),
microbial superantigens
Allergy Likely Unlikely
Inflammation Th2 driven, eosinophilic Th1 or Th2 driven, neutrophilic and/or
eosinophilic, innate immunity, Th-17,
Proteases
Environment Allergens, daycare,
school and workplace
Workplace, dwelling type (house,
apartment and Institutional)
Current Opinion in Pulmonary Medicine 2010,16:55–59

15. Pathogenesis
• Airway inflammation plays a major role in asthma
including AIE
• IL-6, prominent in older adults with generalized
inflammation, may increase IL-17 and decrease Treg
cells, resulting in predominately neutrophilic
inflammation in the lungs
• Resistance of different inflammatory cells to initiate
apoptosis in asthmatic patients, causing persistence of
airway inflammation
Current Opinion in Pulmonary Medicine 2010, 16:55–59

16. Risk factor
• Genes, and especially epigenetic changes
• Respiratory infections
▫ viral [rhinovirus and RSV]
▫ bacteria
▫ Superantigen (staphylococcal enterotoxins)
• Atopy
• Obesity
▫ increased inflammation and may cause mechanical
impairment of diaphragm excursion
• Female sex
▫  prevalence, hospitalization and higher death rates
Current Opinion in Pulmonary Medicine 2010,16:55–59

17. Studies examining early versus late-onset asthma
Current Opinion in Pulmonary Medicine 2010,16:55–59

18. Special characteristics of asthma in elderly
• Lung function decreases with age, and decrease
greater in men
• reduced response to bronchodilators and
glucocorticoids
• Rarely IgE mediated, and often develops with
component of irreversible airway obstruction
• immunosenescence
▫ Naive T cells decrease, memory T cells increase, and
B-cell function decreases, but lesser decrease in
innate immunity
▫ Eosinophil function remains the same, but neutrophil
numbers increase
J Allergy Clin Immunol 2010;126:681-7.

19. Age-related decline in FEV1 by strata in men aged 18–80 years
derived from linear mixed effects models
Mean FEV1 is corrected for height, weight, and age at first survey
Am J Respir Crit Care Med Vol 171. pp 109–114, 2005.

20. Special characteristics
of asthma in elderly
1. great variability in the
duration and severity of the
disease
2. onset can have been at
any time since childhood
but more often begins in
middle age or later
3. many of these patients
have severe irreversible
obstruction unrelated to the
duration of the diseaseThese patients are random selection
of approximately 1,200 patients 65
years of age or older given diagnosis
of asthma at Mayo Clinic in 1993
J Allergy Clin Immunol 2010;126:681-7.

21. Special characteristics of asthma in elderly
• Coexistence of asthma and COPD in elderly
patients due to
▫ Cigarette smoking
▫ Exposure to airborne endotoxin
▫ Latent adenovirus in respiratory epithelial cells
J Allergy Clin Immunol 2010;126:681-7.

22. Non-proportional Venn diagram of chronic obstructive pulmonary
disease (COPD)
Thorax. 2008 September ; 63(9): 761–767.

23. Asthma and COPD
Asthma-specific feature COPD specific feature
• Reversibility
• Airway inflammation (E )
• Th2-cytokine pattern
• Reduced elastic recoil due to
edema
• Perfusion of underventilated
areas (esp. during
exacerbation)
• Irreversible airflow
obstruction (predominantly)
• Destruction of alveoli
• Reduced elastic recoil due to
loss of lung tissue
• Ventilation of underperfused
area
• Response to anticholinergic
agents
Clinical immunology, Principles and Practice.Third edition.
Common feature
- Airflow obstruction
- Shift of tidal breathing towards TLC during exacerbation

24. Clinical and physiological characteristics of obstructive airway syndromes
Thorax 2009;64:728–735.

25. Percentage of adults (by gender) with airflow obstruction who have an
overlap syndrome with increasing age. Males are shown in the black bars and
females in the white bars
Thorax 2009;64:728–735.

26. Differentiating features of COPD and asthma
COPD Asthma
(early-onset)
Asthma (late-
onset)
Overlap
syndrome
Onset Mid life Early life 65 y or older May have history
of asthma in early
life
Risk factors Smoking Atopy, airway
hyperresponsiven
ess
Atopy, irritant
exposures
Smoking, aging
Symptoms Slowly progress Intermittent, worse
at
night/morning
Intermittent, poor
perception of
symptoms
Slowly
progressive
Family history May be present Frequently
present
May be present May be present
FEV1/FVC <70% ≥70% <70% <70%
FEV1% predicted <80% >80% <80% <80%
Bronchodilator
response
Absent present present Absent
J Allergy Clin Immunol 2010;126:702-9.

27. Diagnostic challenges of asthma in the elderly
• confused with COPD and heart failure
• Spirometry
▫ underutilized in primary care setting
▫ parameters define asthma in aging population
▫ performance of effective testing
• postbronchodilator PFT
• Alterations in perception of airway obstruction due to
aging
▫ underestimation of disease severity and delay in seeking advice
• Several systemic comorbidities may coexist with AIE
Current Opinion in Pulmonary Medicine 2010,16:55–59

28. Diagnostic details that affect management after the
diagnosis of asthma has been established
• Age at onset
• Upper airway disease, sinusitis, and polyps
• ADR
▫ Aspirin, beta blocker, including eyedrops, and ACEI
• Coexisting diseases
• Pack-years of cigarette smoking or passive exposure
• Past or present occupational exposures
• Domestic exposures to irritants, allergens, and
stimulants of innate immunity
• Persistent airway obstruction despite therapy
• Total and specific IgE levels
• Abnormal chest radiographic or CT scan results
J Allergy Clin Immunol 2010;126:681-7.

29. Management challenges of asthma in the elderly
• Physicians overlooking appropriate treatment of asthma
• Patient do not want to or cannot afford to take
‘prophylactic’ or preventive medicines
• psychomotor and cognitive disabilities affect choice of
inhaler delivery systems
• drug interactions and increased incidence of ADRs
• lack of many drug trials involving elderly asthma
Current Opinion in Pulmonary Medicine 2010,16:55–59

30. Details of asthma control important in elderly
patients
• Control exposure to environmental agents
• Monitor skill of inhaling aerosol medications
• Establish ‘‘personal best’’ FEV1
• Add oral medications, such as leukotriene antagonists or
low-dose theophylline, for patients with severe asthma
• If there is a concern about cardiotoxicity of b-adrenergic
agonists, substitute anticholinergic aerosols
• Manage osteoporosis and other coexisting diseases
• Influenza and pneumococcal immunization
J Allergy Clin Immunol 2010;126:681-7.

31. Beta agonist
Chest 2004;125;2309-2321

32. Beta agonist
Chest 2004;125;2309-2321

33. Beta agonist
Chest 2004;125;2309-2321

34. Beta agonist
Chest 2004;125;2309-2321

35. SMART trial
• possible link between LABA and respiratory-related
deaths in asthmatic patients >12 yr ( mean 40)
• subjects using LABA without ICS compared with
placebo, occurred primarily in African Americans
• respiratory-related deaths
▫ (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41)
• asthma-related deaths
▫ (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34)
• combined asthma-related deaths or life-threatening
experiences
▫ (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89)
CHEST 2006; 129:15–26.

36. Anticholinergic Medications
• Cochrane review (22 studies)1
▫ statistically significant improvements in daytime dyspnea and peak
flow measurements in patients treated with inhaled anticholinergic
agents compared with placebo
▫ no difference between anticholinergic plus SABA and SABA alone in
the improvement of symptoms or PEF (maintenance Rx)
• Meta-analysis (23 RCT)2
▫ Reduction in hospitalization and improved spirometric function with
combination therapy when compared with SABA alone
• asthma guidelines recommend combining inhaled
ipratropium with SABA therapy in moderate or severe
asthma exacerbations
1.Cochrane Database Syst Rev. 2004;3:CD003269
2.Thorax. 2005;60:740-746.

37. Corticosteroids
• Adult patients with asthma did not sustain a significant
loss of BMD from ICS use1
▫ Adverse effects may be seen only after many years of high-dose
inhaled corticosteroid use
• study of 38,325 (age>66) more using ICS or INCS2
▫ increased risk of ocular HT and open-angle glaucoma with
prolonged administration (OR 1.44; 1.01-2.06)
• study of 3677 patients (aged >70) inhaled
beclomethasone or budesonide ( 1mg/d, >2 yrs.)3
▫ increased risk for cataracts (OR 3.40; 1.49-7.76)
1. CHEST 2003; 124:2329–2340
2. JAMA. 1997;277:722-727
3. JAMA. 1998;280:539-543.

38. Leukotriene Receptor Antagonists
• ACCEPT trial
▫ 4-week open-label trial of zafirlukast that included
321 asthmatic patients (aged >66)
▫ statistically significant improvements in symptoms
and morning PEF with zafirlukast, ( less than in
younger groups )
▫ Side effects in seniors were only slightly more
common than in younger adults (17.5% vs 18.8%)
Ann Allergy Asthma Immunol 2000;84:217–225.

39. Anti-immunoglobulin-E Therapies
• 2511 asthmatic patients aged 6 to 75 years
▫ Omalizumab use was associated with a reduction of
asthma exacerbations by 38% and emergency
department visits by 47%
▫ subgroup analysis showed beneficial effects among all
age groups, improvements in patients aged > 65 years
did not reach statistical significance
Allergy 2005: 60: 302–308

40. Drugs that decrease theophylline clearance
Drugs & Aging 2000 Nov; 17 (5): 385-397

41. Potential
issues with
technique of
inhalation
treatment for
older people
Lancet 2010; 376: 803–13

42. Model
representing the
multidimensional
assessment of
asthma in older
adults with
multidisciplinary
intervention
Lancet 2010; 376: 803–13

43. Take home message
• Asthma in elderly
▫ Underdiagnosis and undertreatment
▫ Multidimentional aspects of aging, disease
concurrence and comorbidity and patient
preference