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Asthma in the elderly (AIE) is under diagnosed and under treated and there is a paucity of knowledge. The National Institute on Aging convened this workshop to identify what is known, what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of AIE. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger individuals but co-morbid illnesses and the psychosocial effects of aging may affect the diagnosis, clinical presentation and care of asthma in this population. At least two phenotypes exist among elderly asthma; those with long-standing asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiological mechanisms of AIE are likely to be different from those seen in young asthmatics and these differences may influence the clinical course and outcomes of asthma in this population.
The proportion of people over age 65 in the U.S. is currently about 13 percent, but is projected to grow from about 40 million in 2005 to over 86 million by 2050 accounting for 25 percent of the population. The age group with the largest growth will be those over age 85, which is estimated to be over one million by 2050(1;2). In 2004, the U.S. prevalence of asthma for those 65 or older was 7%, with 1,088,000 reporting an asthma attack in the previous 12 months(3). Older asthmatics are more likely to be under-diagnosed, undertreated(4;5) and hospitalized than younger asthmatics(3). They also have the highest death rate (51.3 per million people) of any other age group(6). Older women are hospitalized more than twice as often as older men.
Asthma in older adults is superimposed on a background of aging-related changes in respiratory and immune physiology, and often on multiple diseases and conditions common in older age. Recognizing the paucity of research, the many challenges that exist in the recognition and treatment of asthma in older adults, and the opportunity to bridge geriatrics and the clinical specialties that focus on asthma, the National Institute on Aging (NIA), sponsored a “Workshop on Asthma in the Elderly” in Herndon, VA, on September 8–9, 2008. The workshop was planned by a committee of six physician-scientists from U.S. academic institutions or from the Division of Geriatrics and Clinical Gerontology in the NIA. The Planning Committee selected speakers and participants for their expertise in asthma, pulmonology, allergy/immunology, primary care, emergency medicine, geriatrics, and/or gerontologic science (see list of participants in the Appendix). The immediate goals of this workshop were to summarize current understanding about the mechanisms of asthma in older persons and to identify knowledge gaps and research opportunities leading to improved medical care and health outcomes for older people with asthma. These research opportunities are discussed in the body of this report and summarized in Table 1.
In addition, the NIA, in collaboration with the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID) recently issued a set of program announcements inviting research proposals on asthma in older adults (http://grants.nih.gov/grants/guide/pa-files/PA-10-263.html, http://grants.nih.gov/grants/guide/pa-files/PA-10-264.html, and http://grants.nih.gov/grants/guide/pa-files/PA-10-265.html.)
It is a central principle of gerontology that aging itself is not a disease(10). Yet, there are physiological changes within organs, tissues and cells that result in diminished functional reserve and thereby increased susceptibility to stressors and/or disease. A second principle is that these aging changes are highly variable and account for the great constitutional heterogeneity among older people from very `fit' to very `frail'. In fact, the concept of frailty, both causes and consequences, has become a focus of concentrated gerontologic investigation.
At the root of these age-associated physiological changes are a number of genetic, epigenetic and environmental factors(11). Molecular damage accumulates over time, and the capacity for DNA repair declines(12). Cellular senescence, believed to be the consequence of accumulated DNA and protein damage and reduced proliferative capacity, is becoming increasingly understood at the molecular level(13). However, just how this correlates with the phenotypic changes of advanced age remains incompletely understood(14).
There has been much written about cellular senescence and the events that lead up to cell death(15–17). After a finite number of divisions, normal somatic cells invariably enter a state of irreversibly-arrested growth, a process termed replicative senescence(18). In fact, it has been proposed that escape from the regulators of senescence is the antecedent of malignant transformation. However, the role of replicative senescence as an explanation of organismal aging remains the subject of vigorous debate. The controversy relates, in part, to the fact that certain organisms (e.g., drosophila, C. elegans) undergo an aging process, yet all of their adult cells are post replicative.
What is clear is the loss of proliferative capacity of human cells in culture is intrinsic to the cells and not dependent on environmental factors or even culture conditions(18). Unless transformation occurs, cells age with each successive division. The number of divisions turns out to be more important than the actual amount of time passed. Thus, cells held in a quiescent state for months, when allowed back into a proliferative environment, will continue approximately the same number of divisions as those that were allowed to proliferate without a quiescent period(19).
The question remains whether this in vitro phenomenon is relevant to animal aging. One suggestive observation is that of fibroblasts cultured from samples of old skin undergo fewer cycles of replication than those from young(20). Furthermore, when various species are compared, replicative potential is directly and significantly related to life span(21). An unusual β-galactosidase with activity peaks at pH6 has proved to be a useful biomarker of in vitro senescence because it is expressed by senescent but not presenescent or quiescent fibroblasts(22). This particular β-galactosidase isoform was found to have the predicted pattern of expression in skin from young and old donors with measurably increased levels in dermal fibroblasts and epidermal keratinocytes with advancing age(22). The nature of the expression of this in vivo biomarker of aging in other tissues will be important to discern.
For clinical investigators frailty has proven hard to define primarily because of the seemingly insurmountable heterogeneity inherent in geriatric populations on the basis of these variable rates of organ system decline and the presence or absence of one or more diseases(9). Yet, regardless of the pathway taken to frailty, the clinical picture has common features including a reduction in lean body mass (sarcopenia), loss of bone mass (osteopenia), cognitive impairment, functional decline and anemia. On the basis of data derived from large cohorts of elderly individuals, Fried and colleagues have offered an operational definition of frailty incorporating an assessment of five specific characteristics to ascribe a Frailty Index(23). On this 5-point scale, a score of 3 or more has been shown to be independently predictive of a range of adverse clinical outcomes including acute illness, falls, hospitalization, nursing home placement, and early mortality(23–25). Furthermore, simple performance measures, such as the assessment of walking speed, are predictive of important outcomes including survival(26).
With the phenotype better defined, attention has shifted to pathophysiology. Although frailty may occur in the absence of a diagnosable illness, the fact that some become frail and others don't suggests an inherent or acquired variability in homeostatic pathways. Recent evidence from observational studies has raised suspicion that dysregulated inflammatory processes are involved, if not central to of the variable patterns of aging. Elevated serum levels of certain proinflammatory cytokines, most notably interleukin-6 (IL-6), are increasingly present with advancing age and to a greater extent with frailty(27;28). Furthermore, the appearance of this and other inflammatory markers have been associated with a number of adverse clinical outcomes including decreased strength and mobility, falls, dementia, and mortality(27).
From the perspective of those who study aging, there is an important distinction made between median (life expectancy) and maximum life span. Over the past several decades, with the advent of modern sanitation, refrigeration and other public health measures including vaccination and antibiotics, there has been a dramatic increase in median survival(29). Early deaths have been diminished and more individuals are reaching old age. In the United States today, life expectancy now approaches 80 years(30). Median survival is what concerns public health officials and health care providers but for those studying the biology of aging, it is maximum survival that is the focus of greatest attention. It is worthwhile to note that it has been estimated that if atherosclerosis and cancer were eliminated from the population as a cause of death, about ten years would be added to the average life span, yet there would be no change in maximum life span(31).
Although several theories have been proposed, none suffice to account for the complexities of aging. Life span is finite and varies generally from species to species and much less so within species. Mice live, on average, 2 ½ years, monkeys 30 years and humans about 90. Among species, larger animals generally live longer than smaller but within species smaller animals are likely to live longer. It is clear that aging is not entirely explained by DNA sequence. For example, mice and bats have only 0.25% difference in their primary DNA sequence but bats live for 25 years, 10 times longer than mice. A commonly held notion is that regulation of gene expression accounts for longevity difference between species.
It is now clearly established that certain specific genes can alter life span, at least in lower animals, but whether these same genes regulate “aging” is still in question. For example, transgenic drosophila expressing increased copies of the free radical scavenging enzymes, superoxide dismutase and catalase, live on average, a third longer than the appropriate controls(32). In even lower species (e.g., yeast and nematodes), the identification of specific genes that influence life span(33;34) has led to the optimistic impression that analogous genes in higher organisms will lead greater insights into the aging process. Yet, the identification and functional analysis of analogous genes in humans remains elusive.
The oldest human being alive today is approximately 120 years old. What is intriguing is that the record has remained stable, unchanged by the public health initiatives mentioned above. In fact, there has been some recent data presented that the maximum survival is actually declining in the United States(35;36). What is interesting is that, unlike the public health initiatives in humans in which median but not maximum survival has been enhanced, experimental interventions in lower species have resulted in prolongation of maximum survival. As mentioned above, transgenic drosophila producing extra copies of superoxide dismutase and catalase survived about 33% longer than controls(32) and similarly, the maximum survival in C57BL/6 mice fed a calorically restricted diet enhanced by 50% or more(37;38). The true mechanisms of aging may well be uncovered with a better understanding of how these interventions effect longer survival.
Future research in aging should attempt to improve our understanding of the basic biology of aging and interventions that retard the aging process. There is a need for the development and application of a standardized definition of frailty for future clinical investigation. Investigations directed at the role of co-morbidities in accelerating the aging process are important. Furthermore, future research should focus on the development of cellular and animal models of typical, delayed, and accelerated aging and of large collaborative networks in which populations and resources can be shared to study aging and frailty. Leveraging on well-characterized existing cohorts whenever possible is recommended.
The lungs like other organs age and exhibit continued loss in function as an individual grows old. Lung function is traditionally assessed by a number of standardized methods. The most common measurement used is spirometry with the determination of FEV1 and FVC. FEV1 and FVC both show continuous falls of between 25 and 30 ml with each year of life after about age 20.(39) The cause of this fall is usually attributed to the loss of the driving forces for airflow as a result of reduced respiratory muscle performance and/or loss of static elastic recoil.(39;40) The fall in FEV1 in asthma is largely a function of the fall of FVC due to the rise in residual volume.(41) Stiffening of the chest wall and reduced respiratory muscle performance result in a fall in total lung capacity and a rise in residual volume due to ever increasing closing volume.(42) Accordingly, these aging processes lead to airflow limitation that may be hard to distinguish from an active disease process.
Not all older individuals are able to perform spirometry, especially those with decreased cognition, coordination and frailty. In addition spirometry is effort dependent and the very old may tire quickly. Techniques of imaging and measures of lung function not requiring effort (i.e. forced oscillation) should be utilized in future studies to extend our knowledge about lung structure-function relationships at the very end of life.
Bronchodilator responses are known to be less marked in the elderly perhaps as a consequence of the aging effects attributed to the emphysema-like state of the senile lung(43); however this would not explain the slow temporal response to bronchodilators (BD). Other studies do not find such age-related BD differences. Furthermore, while methacholine responsiveness has been reported to increase with aging, the exact mechanism for this is not apparent.
An increased incidence and prevalence of many lung diseases occur with age. Alterations in immune function increase the risk of many of these diseases. Studies of systemic immunity suggest that sustained antigenic stress over a lifetime leads to a decline in naïve T cells, an accumulation of memory T cells, a decline in T cell repertoire and B cell functions, but a lesser decline in innate immunity(43;44). Little is known about what happens to the immune/inflammatory pathways in older asthmatics. The immune system changes with aging will be discussed in more detail in the section on pathophysiology.
In the United States, the National Health Interview Survey asks questions regarding lifetime history of asthma, current asthma prevalence, and asthma attacks in the last 12 months(3). For all age groups, asthma prevalence has been steadily increasing since 1980. For the 65 and older age group, asthma is consistently more prevalent in females than males(3). The National Center for Health Statistics tracks data on physician encounters for asthma. The national ambulatory care survey reported that those 65 or older have the second highest rate of outpatient office visits after those aged 0 to 4. Those 65 and older did not have significantly different emergency room visits than the other adult age groups. The 65 and older age group accounts for a greater proportion of hospitalizations (23%) than the size of its population (13%) would indicate.
Not surprisingly, the elderly population is a high user of medical resources for the treatment of asthma. Hospitalizations and emergency department visits are more common for these patients than other adult cohorts. Some of the increased costs are related to co-morbid disease. For example, the presence of co-morbid COPD increases the risk of an asthma related hospitalization in Medicare patients 3.6-fold; respiratory medical costs almost 6-fold and total medical costs 2-fold. Elderly females appear at greater risk than elderly males(45–48)
Asthma mortality increased steadily from 1980 until it peaked in 1998. The highest mortality rates for asthma occur in the 65 and older age group. In fact, the increase in asthma mortality between 1979 and 1989 was primarily driven by the 65 and older age group. In addition, the decline in asthma mortality between 1999 and 2005 was most evident in this age group. Elderly women with asthma tend to have higher mortality rates than elderly men with asthma.
One reason for increasing prevalence of asthma in the elderly may be due to improved longevity of the population. Also, increased office visits for asthma in the elderly may be responsible for fewer attacks. Increasing hospital admissions may account for decreased mortality. By continuing to gather surveillance data on asthma, reasons for these trends may become clearer. In addition, surveillance data helps to focus intervention efforts in areas of greatest need.
In the Cardiovascular Health Study, a large community-based cohort of individuals over the age of 65, questions were asked that were relevant to asthma that provided more insight into the prevalence and impact of asthma in this population(5;49;50). Definite asthma was defined as a positive response to the questions indicating that they had current asthma and that a physician confirmed the diagnosis. Probable asthma was defined as a history of wheezing in the past year associated with chest tightness or breathlessness. Excluding smokers and those with a diagnosis of congestive heart failure, 4% of individuals had definite asthma and 4% had probable asthma. Among those who smoked, 11% had definite asthma and 14% had probable asthma. Among non-smokers 185 individuals were identified who had definite or probable asthma 76% were women, and 20% were over the age of 80. The age of asthma onset was spread approximately evenly among decades. 27% had late onset of disease after age 60 and 25% had onset of disease before age 20. As expected, respiratory symptoms in the older asthmatics were more prevalent with a 2–5-fold increase in cough, phlegm, wheezing, and dyspnea. Dyspnea on exertion was 1.6 fold more likely to be present in asthmatics than those without the diagnosis. Lung function was reduced in those with a diagnosis of asthma. The mean forced expiratory volume at 1 second (FEV1) was 77% predicted in those with definite asthma and 89% predicted in those with probable asthma compared to 96% in those who did not have asthma. 41% of those with a diagnosis of asthma had airflow obstruction below the 5th percentile for the age group, and peak flow lability was increased. Elderly asthmatics reported the most common trigger was a viral infection in 58% compared to animal allergies in 30%. Two-thirds reported seasonal worsening. Asthma had a significant impact on quality of life, with 35% of definite or probable asthmatics reporting a fair or poor health status compared to 17% of the elderly without asthma. 60% of definite asthmatics reported seasonal allergic rhinitis compared with only 30% in the non-asthma group. Despite the high prevalence and morbidity of asthma in this population, inadequate treatment was common. Only 40% of those with definite asthma had a rescue albuterol inhaler, only 30% had an inhaled corticosteroid(5;49;51;51;52).
The pathophysiology of asthma in the older adult is poorly understood and is understudied. Many questions about this issue remain; Is asthma the same disease in older adults as it is in children and younger adults? Is late onset asthma (LOA)(asthma that starts in middle age or older) different from long-standing asthma (LSA) (asthma of early onset that has persisted into older adulthood)? If LOA and LSA are the same disease, then the diagnosis and treatment should be similar. However, if LOA and LSA are different phenotypes, or at least have a different etiology and pathophysiology, then the diagnosis and treatment may differ. (Table 2)
The traditional view of disease susceptibility has been expanded to include epigenetics to account for the influence of environmental factors and aging on the genomic blueprint. Epigenetics is defined as heritable changes in gene expression that occur without alterations in DNA sequence. It is the process by which genotype interacts with environment to produce a phenotype, and explains differences between cells, tissues, and organs despite identical genetic information. Genes function in a milieu determined by the developmental and environmental history of the cell, which constitutes the epigenotype(53;54). Epigenetic changes or marks can play a major role in human disease(55;56). The most common examples of epigenetic marks are DNA methylation of Cytosine phosphodiester Guanine (CpG) islands by DNA methyltransferases, and chromatin modification of histone proteins, particularly acetylation by histone acetyltransferases (HAT) and histone deacetylases (HDAC)(57;58). The function of epigenetic changes is to regulate gene expression. Epigenetic changes are known to contribute to cancer and autoimmune disease, and are thought to contribute to common diseases including cardiovascular disease, diabetes and the loss of response to stress due to aging(59).
Asthma is a markedly heterogeneous disease and recent evidence suggests that environmentally induced epigenetic changes contribute to asthma phenotypes and that airway inflammation in asthma and COPD may involve epigenetic regulation(57;58;60). Methylation patterns and chromatin structure change with age and are thought to contribute to the rise in the incidence of common diseases that begin in middle age(55;61). The incidence of asthma in the elderly resembles the incidence of common diseases. Moreover, characteristics and asthma drug response in the elderly asthmatic differ from those in childhood asthma. Compared to younger cohorts, elderly asthmatics have a higher prevalence, higher rates of bronchial hyper reactivity (BHR), more severe asthma and a lower prevalence of atopy. Elderly asthmatics are more difficult to control with drug therapy, have steroid resistance and may respond better to leukotriene receptor antagonists compared to inhaled corticosteroids(62–71). The contribution of epigenetics to differences observed between elderly asthmatics and younger cohorts is unknown. Unlike genetic variants that contribute to disease, epigenetic changes can be reversed and therefore represent potential drug targets(72).
Older asthma patients are less responsive to albuterol treatments given in the emergency room and are more frequently admitted for hospitalization(73). Thus, it appears that the responsiveness to treatment is diminished and the severity of asthma exacerbations is greater. The exact reason for these disparities is not known. Immune cell function decreases with aging, a property often termed “immunosenescence”(74). One often-confusing aspect of immunosenescence is the observation that aging may be associated with opposing immunological effects. For example, T-cell secretion of IL-2, IL-4, or Interferon gamma (IFN-γ) have all been shown to be decreased with aging and also increased with aging(75). It is likely that both phenomena are correct, but are dependent on the context of the immune function. Thus, the effect of aging on T-cell function in the context of allergen stimulation may be different than the effects of aging on T-cell function in the context of viral infection. Given that asthma is an inflammatory disorder of the airway, it is of interest to determine whether asthmatic airway inflammation of the elderly may differ from that of younger asthma patients and thus represent a distinct phenotype of asthma. These changes may have implications for susceptibility to exacerbations due to virus or other pathogens as well as response to treatment.
The aging process has been shown to exhibit changes in airway inflammation. An examination of the cellular composition of bronchoalveolar fluid from 19 to 83 year old subjects, without history of allergies, pulmonary disease or gastroesophageal reflux, showed increased airway neutrophilia as well as increased numbers of CD4+ T cells(76;77). The T cells also appeared to be more activated in the elderly with increased expression of HLA-DR and CD69. The increase in airway neutrophils with aging has also been observed in asthma subjects(78). Since there is a phenotype of severe asthma characterized by a predominantly neutrophilic airway inflammation(79), the question arises as to whether the increased presence of neutrophils contributes to a greater severity of asthma in the elderly.
Some of the prominent inflammatory cells recruited into the airway in asthma are eosinophils, neutrophils and T cells, which are capable of secreting numerous inflammatory mediators including leukotrienes and cytokines. It is not known whether immunosenescence affects the production of these mediators in elderly asthma patients, either at baseline or during an exacerbation of symptoms. Furthermore, it is not known whether age-related changes in their production would have any implication for the clinical presentation or management of asthma in the elderly. Peripheral blood eosinophils were isolated from younger (20–40 years old) and older (55–80 years old) subjects for in vitro functional assays. The eosinophil effector functions of degranulation and superoxide production were diminished in the older subjects as compared to the younger asthma subjects. In another study examining the expression of neutrophil mediators in younger and older asthma subjects, there is decreased baseline expression of LTB4 in the sputum of older asthma subjects despite greater numbers of neutrophils(80). Whether these findings have implications during an asthma exacerbation has yet to be determined. Nevertheless, the results demonstrate age-related changes in the function of an inflammatory cell considered pathognomonic for allergic asthma and raise the question of whether additional effects of immunosenescence are relevant to airway inflammation in asthma.
There have been several studies of animal models to address age-related changes in the airway inflammation induced by allergen challenge of sensitized, aged animals. These studies yielded conflicting results and there is concern that the animal models do not accurately represent the chronic features of human asthma with seasonal allergen exposure and intermittent exacerbations. The aged animals were both sensitized and challenged at old age, in contrast to the typical elderly human asthma patient who may be exposed to allergens for several decades.
Typically, nasal and ocular symptoms upon exposure to allergens diminish with age. Allergen-triggered asthma symptoms also diminish with aging. The Epidemiology and Natural History of Asthma (TENOR) study examined the natural history of asthma in older (> 65 years old) compared to younger patients and found that older asthmatics had lower total IgE levels, fewer positive skin prick tests, and less concomitant allergic rhinitis or atopic dermatitis(81). Several studies have demonstrated age-related declines in total IgE and allergen-specific IgE levels(82–87), suggesting that this may be the explanation for the decline in allergy symptoms. There is also evidence for an age-related decline in skin-prick test responses to allergens(88). However, the relationship between total IgE and allergic disease persists in the elderly, such that subjects with greater levels of IgE remain more likely to have allergic rhinitis or asthma(89;90).
Given the changes in allergic inflammation with aging, one might conclude that asthma in the elderly should be milder. However, there are several other common triggers for exacerbations of asthma including irritants (e.g. cold air) and respiratory infections. Estimates suggest that up to 80% of asthma exacerbations in adults are caused by viral upper respiratory infections(91).
The role of environmental exposures and allergy in older asthmatics is largely unknown. In the general population, evidence regarding the effect of indoor pollution on asthma is summarized in “Clearing the Air: Asthma and Indoor Air Exposure” by the Institute of Medicine for the Environmental Protection Agency in 2000(92). Evidence was reported for asthma development related to house dust mites and for asthma development associated with environmental tobacco smoke in preschool children. The report also showed evidence for causation of asthma exacerbations for house dust mite, environmental tobacco smoke (in preschool children), cat, and cockroach; an association with exacerbations was found for dogs, fungi, formaldehyde, and rhinovirus. In addition, evidence associating exacerbation of asthma-related symptoms with self-reported damp air was reported in a review of Damp Indoor Spaces and Health(93;94). There are only a few studies that have evaluated the role of atopy in elderly with asthma. One large national study of allergy skin tests that included older adults(95) and several small studies of allergy skin tests in older adults with asthma(81;96–103) were reviewed. Allergy skin tests were positive in 8–12% of all older adults. Prevalence of positive skin test or specific IgE to at least one allergen in older adults with asthma ranged from 0–75%. Those whose asthma had unknown age of onset ranged from 27–60%, those with onset prior to age 41 ranged from 56–62%, and those with onset greater than age 41 ranged from 0 to 24%. (Table 3)
While there were no studies of allergen room exposure or bronchial challenge in older adults, neither prick-puncture skin tests nor specific IgE predicted nasal challenge response to dust mites.(104) Safety concerns for allergen challenges in older adults are unresolved. Technical limitations of allergens, environmental measurements, and age-specific norms and cut-off levels for laboratory and physiologic tests are needed. A few epidemiologic studies suggest an association between outdoor environmental exposures and emergency department or hospital admissions in older adults(105;106).
In summary, studies of the general population suggest a causation or association between indoor air pollutants and allergy exposure and asthma. There are several small studies suggesting higher levels of positive allergy tests in older adults with asthma than in the general population of older adults. When age of onset is considered, asthma with an early onset (before age 41) has a much higher association with positive allergy tests than late onset asthma.
Viral respiratory infections are common precipitants of asthma exacerbations during childhood. In approximately 80% of children with acute asthma exacerbations, a respiratory virus can be detected, with rhinovirus being the most frequent pathogen identified(107). Although it is likely that viruses also lead to exacerbations of asthma in older adults, comprehensive studies regarding the rates and specific pathogens are lacking. Several issues have made defining the role of viruses in adult asthma problematic and include; difficulty distinguishing COPD from asthma, lack of sensitive diagnostic tests, and issues with asymptomatic infection. A number of investigators have explored the incidence of viral infection in adult asthmatics(91;108;109). Older studies using viral culture and serology for diagnosis demonstrated infection rates of 10–29%(109). In contrast, more recent studies which include reverse transcription polymerase chain reaction (RT-PCR) have shown significantly higher infection rates of 44–55%(91;108). Similar to results found in children, rhinoviruses are the most frequently detected pathogen. Few older persons were included in these studies where the mean ages of subjects were 30–39.
The incidence of acute respiratory infections decreases steadily with advancing age and rates of viral infection in older adults are influenced by place of residence(110). Among community dwelling older adults rates of acute respiratory infections are roughly 1–2% per year, whereas, rates in senior daycare centers and long-term care facilities are substantially higher at 6–11%(111). In addition, the epidemiology of respiratory infections can be quite complex in these semi-closed populations with multiple pathogens circulating simultaneously(112). Influenza A, Respiratory Syncytial Virus (RSV) and human metapneumovirus (hMPV) are the most commonly identified viruses among older persons hospitalized with acute cardiopulmonary conditions(113;114). Most individuals who require hospitalization during a viral respiratory infection have underlying heart and lung conditions. Although studies to date have largely focused on the role of viruses in COPD exacerbations it is reasonable to extrapolate infection rates and specific pathogens from these studies to older adults with asthma. Johnston et al. in Ontario, Canada found a seasonal peak in emergency room visits for all acute respiratory infections as well as exacerbations of both COPD and asthma for persons younger and older than 50 years of age(115). All the common respiratory viruses have been associated with COPD exacerbations and, depending on the methodology and season of study, the specific rates of influenza, RSV, parainfluenza viruses, coronaviruses, hMPV, and rhinoviruses vary(116;117). Wheezing appears to be a common symptom in older adults infected with any of the respiratory viruses, particularly with RSV and hMPV, and 7% percent of adults hospitalized with RSV will have a discharge diagnosis of asthma(114;118).
Since most adult infections represent re-infection, the viral load in respiratory secretions tends to be low, making detection with conventional techniques difficult. Viral culture and rapid antigen testing, which can be used successfully in children, have poor sensitivity in older adults. The use of molecular diagnostics has vastly improved the ability to detect a number of viruses such as RSV, parainfluenza, and rhinoviruses and allows the detection of hitherto uncultivable agents such as human metapneumovirus (hMPV) and coronaviruses.
Viral infections appear to aggravate reactive airway disease by a number of different mechanisms. It has been postulated that viral infection disrupts the negative feedback loop of acetylcholine on the M2 receptor, leading to increased levels of acetylcholine and increased constriction of bronchiolar smooth muscle(119). Infection of the respiratory epithelium also induces chemokines, cytokines, immune and growth factors, which result in a proinflammatory state(120;121). Immunosenescence may affect the ability of older adults to clear viruses efficiently and thus, greater and more prolonged inflammation may result.
In summary, respiratory viral infections are common among older adults and are likely precipitants of acute asthma exacerbations. Furthermore, respiratory viral infections may likely precipitate the onset of LOA, although this needs to be further examined.(122) Comprehensive studies regarding the rates and specific pathogens are lacking in older adults. Distinguishing COPD from asthma, lack of sensitive diagnostic tests, and issues with asymptomatic infections make it difficult to define the role of infections in older adults.
Classic symptoms of asthma in the elderly are mostly similar to younger asthmatics(4;96). Data on the clinical features of asthma in the elderly has been derived from both longitudinal community surveys and case studies (5;64;97;98;122–124). Most patients complain of episodic wheezing, shortness of breath, and chest tightness. These symptoms are often worse at night and with exertion and like younger asthmatics are often precipitated by an upper respiratory tract infection. In fact, the majority of elderly patients who develop asthma after age 65 have their first asthmatic symptom preceded immediately by or concomitant with an upper respiratory tract infection(122). Asthma can often be triggered by environmental exposures such as aeroallergens, irritants (cigarette smoke, household aerosols, paints), strong odors (perfumes), and inhalation of metabisulfites (found in beer, wine and food preservatives). Asthmatic symptoms may also be triggered by medications, such as aspirin, non-steroidal anti-inflammatory agents, ACE inhibitors or beta-blockers, commonly used by this patient population. This emphasizes the need for the physician to perform a comprehensive review of medications taken by the older asthmatic patient Studies have consistently shown that elderly patients and their physicians frequently overlook symptoms caused by asthma(5;73;125). Several factors contribute to the under diagnosis and misdiagnosis of asthma. One reason, shown in large community studies, is that most patients first develop asthma in childhood or adolescence and many physicians have had the misconception that asthma is a childhood disease. Another important reason is that the symptoms of asthma are more commonly associated with other diseases seen in this age group. The symptoms of asthma in the elderly are therefore non-specific and may be caused by conditions that mimic asthma. The differential diagnosis of asthma in the elderly is greater than seen with younger asthmatics and includes: congestive heart failure, emphysema and chronic bronchitis (COPD), chronic aspiration, gastroesophageal reflux (GERD), and tracheobronchial tumors. Co-morbid illnesses and the psychosocial effects of aging may also profoundly affect the diagnosis, clinical presentation and care of asthma in the elderly. One particular diagnosis that is often difficult to detect and frequently overlooked by the patient and physician until the condition is advanced is upper airway obstruction (UAO), including the extrathoracic and intrathoracic central airways. Common etiologies of UAO include malignancy, infection, inflammatory disorders, trauma, and extrinsic compression related to enlargement of adjacent structures (such as an enlarged thyroid gland). It appears that malignancy and benign strictures related to airway instrumentation (e.g. endotracheal intubation and tracheostomy) are becoming increasingly more prevalent in the older age group.
Distinguishing chronic asthma from COPD may be very challenging and in some patients asthma cannot be distinguished from COPD with widely available diagnostic tests. The management of these patients may have similarities to that of asthma. The distinction between long-standing asthma and COPD can be difficult to define precisely. The Lung Health Study showed that methacholine airways reactivity is present in many patients with mild to moderate COPD – 63% of men and 87% of women. Approximately 85% of patients with tobacco-related COPD demonstrate bronchodilator reversibility at least once on repeated testing sessions. The distinction between COPD and asthma may be confounded by either the co-existence of the two common disease entities, the progression of common pathobiologic mechanisms induced by different environmental agents, or different disease mechanisms leading to an overlapping clinical syndrome.
It has been known for more than a century that early morning wheezing is a prominent symptom of congestive heart failure. It has been called cardiac asthma as it can mimic the clinical picture of typical asthma. Usual symptoms of gastroesophageal reflux in the elderly, such as vomiting and heartburn, may be absent. In a study of elderly patients with esophageal reflux proven by intraesophageal pH monitoring, chronic cough, hoarseness and wheezing were present in 57% of patients(126). In addition to causing asthma-like symptoms, there is also evidence that GERD may be a cause of worsening asthma.
Shortness of breath is a common symptom in the elderly and is most commonly caused by heart or lung diseases. It is usually experienced during exertion. Shortness of breath at rest is not typical of heart disease or lung diseases such as COPD or interstitial lung disease, except in advanced stages. When present it should prompt an investigation for asthma as sudden bronchospasm can cause respiratory distress at rest or exercise. Paroxysmal nocturnal dyspnea, typical of congestive heart failure, is found in a smaller number of elderly patients with asthma. Many elderly patients limit their activity to avoid experiencing dyspnea, and others assume that their dyspnea is resulting from their aging process and, thus, avoid seeking medical attention early in their disease process. However, aging per se does not cause dyspnea, and an etiology needs to be always pursued in assessing an elderly patient who complains of breathlessness.
There are several other reasons why the diagnosis of asthma in the elderly may be delayed or not made at all. Elderly patients have been shown to have a reduced perception of bronchoconstriction(127) and this may delay medical intervention. Many elderly patients are fearful of having an illness and dying and are reluctant to admit they are having symptoms. Underreporting of symptoms in the elderly may have many causes including depression, cognitive impairment, social isolation, denial, and confusing symptoms with those of other co morbid illnesses.
Cough is a very prominent symptom and may occasionally be the only presenting symptom. Wheezing, on the other hand, may not be as prominent, and its presence is not very specific and does not correlate with severity of obstruction. Physical examination in elderly patients with asthma is usually nonspecific and may misguide the diagnosis: A negative examination does not rule out asthma and wheezing can be found in a number of conditions such as COPD, recurrent aspiration and “cardiac asthma” (CHF).
Two distinct clinical presentations have been described for asthma in the elderly. These are based on the onset and duration of the disease state(97;124;128). Patients with LOA start having asthma symptoms for the first time when they are 65 years of age or older (some studies have suggested middle age or older). Some studies of elderly asthmatics have shown that as a group, as many as 40% will have their first attack after the age of 40 years(97;98;129). Patients belonging to this group tend to have fewer atopic manifestations, higher baseline FEV1, and a more pronounced bronchodilator response than those with long-standing asthma. Patients with long-standing asthma start having asthma symptoms early in life. Patients belonging to this group tend to have higher incidence of atopic diseases, more severe and irreversible or partially reversible airway obstruction, and more hyperinflation. The duration of the disease in this group is an important determinant of severity and of development of irreversible airflow obstruction(128).
Longitudinal studies of asthmatic populations, whether new onset or long standing, have shown that remission from asthma is uncommon in older age groups occurring in less than 20% of patients(130). This contrasts with asthma in children and adolescents in whom remission of asthma symptoms is common, especially in the second decade of life and may be seen in as many as 60–70% of patients.
Objective measures to confirm the diagnosis of asthma are uncommonly performed in primary care settings. Inhalers are prescribed for patients who are evaluated for asthma-like symptoms and during a follow-up visit, the patient is asked if the controller inhaler reduced the frequency of asthma symptoms or if the albuterol inhaler quickly relieved the symptoms. Such an empiric approach may work most of the time for young patients with mild asthma, but is more likely to result in an incorrect diagnosis, poorly efficacious treatment, or unnecessary medication side effect in older patients.
The onset of wheezing, shortness of breath and cough in an elderly patient is likely to cause concern. Although the adage “all that wheezes is not asthma” is true at any age, it is especially true in the elderly. Diagnosis based on objective measures is essential. Moreover, lung function testing, even in the presence of minimal symptoms, is especially important in this age group since there is thought to be an age-related reduction in the perception of exertional dyspnea in the elderly125. An older patient with chronic, untreated, severe airway obstruction due to asthma may reduce activity to avoid dyspnea and stoically deny impairment of activity. This may reflect either neurocognitive function or changes in lifestyle that favor sedentary activities.
There exist some barriers to lung function testing in the elderly. Spirometry may be difficult to perform in some situations, because of physical or cognitive impairments. However, 80–90% of elderly people are able to perform good quality spirometry when tested by skilled technologists129–133(131–133). The Global initiative for Obstructive Lung Disease) GOLD guidelines for diagnosing the airway obstruction of COPD using a fixed FEV1/FVC <0.70 caused a high misclassification rate in older people134. However, almost all computerized spirometers automatically calculate the appropriate lower limit of the normal range for FEV1/FVC and for FEV1 using race-specific NHANES III reference equations
In addition, it is hard to define the lower limits of predicted normal values in this age group. While complete reversibility of airflow obstruction is frequently seen with young asthmatics, most elderly asthmatics show incomplete reversibility despite continuous intense therapy and many show fixed airflow obstruction as if they have COPD. However, objective measures of lung function such as spirometry and peak flow measurements are generally underutilized in elderly patients and this also contributes to the delay or absence of diagnosis(134;135). Lung function testing is especially important in this age group because of the age-related reduction in the perception of dyspnea seen in the elderly(127). Spirometry is easily performed to determine the FEV1 and ratio of FEV1/FVC is demonstrated with the timed vital capacity maneuver. The flow volume loop, which also measures inspiratory flow, is especially useful when the cause of respiratory symptoms is not known and an upper airway obstruction is in the differential diagnosis. While it may be difficult to perform spirometry in the elderly in some situations because of physical and poor cognitive impairment, studies have demonstrated that between 82 and 93% of elderly patients are able to perform the test properly(131–135). On the other hand it may be more difficult to define the lower limits of predicted normal values in this age group. Traditionally, an FEV1/FVC ratio of less that 70% increases the probability of asthma in an elderly patient with asthma symptoms, but this ratio normally decreases with age because of a decrease in elastic recoil and a ratio lower that 70% may be a normal finding(136).
A brisk response to a short acting bronchodilator may demonstrate the second cardinal feature of asthma, reversible airflow obstruction (“a responder”). When airflow obstruction is found in an elderly patient, attempts should be made to demonstrate reversibility following the inhalation of a short-acting beta-adrenergic agent such as albuterol. Evidence of reversibility (post-bronchodilator FEV1 or FVC increases more than 12% and 200 mL), increases the probability of a diagnosis of asthma. Elderly asthmatics, however, may have an impaired beta agonist bronchodilator response because the number of β-adrenergic receptors on smooth airway muscles is decreased with aging(137). While the bronchodilator response to inhaled beta agonists declines with age(138), this is not the case with anticholinergic agents(139).
Airway obstruction may be absent at the time of testing and further testing may be needed to facilitate the diagnosis. Bronchoprovocation testing with a methacholine challenge can be useful and it is a safe, effective method to uncover asthma in older adults(140;141). A negative test will rule out asthma; a positive test must be interpreted and include an assessment of pretest probability(142). In addition, some studies have shown that bronchial responsiveness is heightened in older adults, and therefore aging may be an independent factor that influences airway responsiveness(143). There is a relationship between the degree of bronchial hyperresponsiveness and prechallenge pulmonary function; a low FEV1 predicts heightened responsiveness(144). Other factors that may contribute to heightened airway responsiveness in the older population are atopy and current or previous smoking history.
Peak expiratory flow variability may be helpful in the diagnosis and follow-up of younger patients with asthma, but poor coordination and muscle weakness in some elderly patients may lead to an inaccurate reading(52;145). A prospective study failed to demonstrate any advantage of peak flow monitoring over symptom monitoring as an asthma management strategy for older adults with moderate-severe asthma when used in a comprehensive asthma management program(146). Other tests such as measuring the carbon monoxide diffusing capacity of the lung (DLCO) have been advocated to distinguish between asthma and COPD, as the DLCO is reduced by parenchymal destruction found with emphysema. Studies have shown however that differences in lung function tests, although statistically significant, cannot be used clinically to separate the two groups of subjects because of a large overlap(147).
There is growing evidence that the airway function of young and middle age asthmatics declines at a greater rate than normal subjects(148–150). The rate of decline increases with increasing age and in those who smoke cigarettes(149;151). In late-onset asthma, there is evidence that lung function is reduced even before a diagnosis is made and declines rapidly shortly after diagnosis(98;152). Thereafter, it remains fairly stable. While the impact on older asthmatics with long standing asthma is variable, in one random survey of 1200 elderly asthmatics over aged 65 years, only one in five patients had normal pulmonary function (FEV1>80% predicted) while a similar number showed moderate to severe airflow obstruction (FEV1<50% predicted) after an inhaled short-acting bronchodilator(153). Since structural changes of emphysema are minimal in elderly asthmatics, except if they are previous smokers, airway remodeling is thought to be the main cause of fixed airflow obstruction.
Nitric oxide (NO) is a gas generated by the action of nitric oxide synthase from the substrates molecular oxygen and arginine. It was originally identified as a biologically important signaling molecule with the properties of an activity previously described as Endothelial-derived Relaxing Factor (EDRF). This molecule is important in regulating vascular integrity and blood flow, and is thought to be a regulator of vascular smooth muscle relaxation.
More recently it has been found that NO may be generated by a variety of inflammatory cells including polymorphonuclear leukocytes, mononuclear cells, and importantly, eosinophils. This finding led to the identification of NO as a molecule present in exhaled breath. Studies of NO exhalation have found that it is increased in infection and inflammation of the airway. Although high levels of NO are found in nasally expired air, studies in pulmonary inflammation have avoided this by redirecting airflow via the oral airway. It has been found that exhaled NO reflects airways inflammation and particularly eosinophilic inflammation. Exhaled NO is increased during the allergy season in atopic individuals. Inhaled glucocorticoids promptly suppress exhaled NO, and do so in conjunction with suppression of eosinophilic inflammatory infiltrates. Studies have demonstrated that monitoring exhaled NO may permit better regulation of asthmatic symptoms, exacerbations and total steroid use than treatments based on guidelines or symptoms. Further, increases in exhaled NO may predict asthma exacerbations.(154) It is of interest that NO in expired air falls after broncho-constrictive stimulation of asthmatic airways.
Little is known of the effects of age on NO in the expired air. It appears that NO production and vascular responses to NO may be diminished in the elderly, but that effect may be overcome by exercise to increase fitness. An unanswered question in airways biology is whether NO is causative of airways dysfunction, a marker for this dysfunction, or an ineffective homeostatic response to airways constriction(155–159).
There is agreement that asthma is both a common and an under-recognized health problem for the elderly that leads to impairments of lung function and quality of health and life. The first question that needs to be addressed is why we need to make such a diagnosis rather than just treat symptoms. Among the reasons that physicians must strive to assign a diagnosis to a patient with a symptom complex is several: The patient is given relief by letting him or her know what is wrong – to give the illness a name which implies a cause, establishes a prognosis, and initiates a treatment plan. Moreover, advancement of understanding of the epidemiology, natural history, pathobiology, and treatment require a definable disease entity. Whether the threshold for diagnostic criteria is set at a high level of sensitivity, a high level of specificity, or a high level of accuracy depends entirely upon the costs and benefits of an incorrect diagnosis vs. a missed diagnosis. For example, enumeration of a disease might require a high level of accuracy, whereas diagnosis of an uncommon difficulty to treat disease (like metastatic cancer) ought to be highly specific. The diagnosis of a common easily treatable disease (like vitamin deficiency) ought to be highly sensitive even if people might be over diagnosed. Asthma tends to be one of those disorders that is relatively easy (though not inexpensive) to treat and has morbid consequences if left untreated, suggesting that the diagnostic criteria ought to be highly sensitive.
Although medical students are taught the rigorous discipline of data collection, differential diagnosis and test confirmation, most physicians do not practice this way. In practice, physicians typically rely on a constellation of signs and symptoms along with demographic characteristics and recent experiences to establish diagnoses through the process of pattern recognition.
There are no shortages of official definitions of asthma, and modifications seem to be added every year. Most of these definitions involve the definition of a clinical syndrome (episodic cough, wheezing and dyspnea); an underlying pathophysiology (airway hyper-responsiveness, variable and reversible airflow obstruction) an underlying biological process (chronic eosinophilic or neutrophilic inflammation of the airways), and an associated morbid anatomy (basement membrane thickening, smooth muscle hypertrophy, and mucus cell metaplasia).
Given this, why is it so challenging to diagnose asthma in the elderly? First, the syndrome of asthma is often confused with other common diseases in the elderly such as chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), paroxysmal arrhythmias, pulmonary emboli, recurrent aspiration, and gastroesophageal reflux (GERD). Second, asthma may often co-exist with these other conditions and it can be impossible to determine which of the two conditions is responsible for the patient's ill health. This diagnostic confusion can be amplified by the different manifestations of asthma in the elderly. Elderly asthmatics can be insensitive to exertional dyspnea because of a sedentary lifestyle. They tend to be less atopic, have an incomplete response to bronchodilators. The elderly without asthma tend to show some signs suggestive of asthma: slower emptying of the lung during forced expiration, decreased lung elastic recoil, and a higher prevalence of non-specific airways reactivity. The hope that formal testing of airways reactivity would prove useful in diagnosing asthma has been lead to disappointment. In young adults, a history of asthma, wheeze or treatment for asthma plus a positive methacholine challenge test is highly specific for asthma (99%), but misses about half of the asthma population(160).
In epidemiologic studies that have examined various criteria for diagnosing asthma, it turns out that the solution is relatively simple. Patients who answer Yes to the question “Have you ever had asthma?” have nearly 100% specificity and 48–100% sensitivity when compared to an independent expert's diagnosis (161;162).
The problem of diagnosing asthma in the elderly is more complicated because of the overlap with COPD. Asthma is typically considered a disease of onset in youth, driven by atopy and eosinophilic inflammation causing reversible airflow limitation. COPD, in contrast, is considered to be a disease of onset in middle age, driven by cigarette smoking and neutrophilic inflammation, leading to irreversible airflow limitation. As evidence presented in this workshop have shown, asthma in the elderly displays many of the features of COPD. The disease may have its symptomatic onset late in life, often is only partially reversible, and is associated with neutrophilic inflammation. Moreover, the current cohort of elderly has a high prevalence of past smoking reflecting the health habits in the United States in the 1940s and 1950s.
The failure to deal with the population of elderly patients who have overlapping signs of asthma and COPD is not just a matter of classification of disease. It has significant health consequences in that such patients are systematically eliminated from clinical trials and are not covered by treatment guidelines. Little is known about how best to treat the elderly patient with asthma who smokes or the elderly patient with COPD who has reversible airflow limitation.
This confusion is manifest by diagnostic coding of diagnosis in older Medicaid patients. Of those who were hospitalized with an initial diagnosis of COPD, 43% had an asthma diagnosis within 3 years. Of those who had an initial hospital diagnosis of asthma, 46% had a diagnosis of COPD within 3 years. Price and colleagues attempted to develop a discriminant function using clinical and demographic information that would separate patients with COPD and Asthma using strict physiologic criteria(161). Although several discriminating characteristics were found, the best diagnostic criteria was only 78% sensitive and only 75% specific.
We need to ask whether it really is important to make the distinction between asthma and COPD in the elderly in terms of prognosis or treatment. One study by Hansen et al. suggests that regardless of whether a person is given a diagnosis of asthma or COPD, the prognosis is mostly determined by the impairment in FEV1(136).
There are a number of ways to measure the impact of asthma in young as well as elderly patients. The assessment of symptoms, functional limitations, quality of life measures, and risk of adverse events are several that have been suggested by current asthma guidelines(163). In addition, measuring a patient's satisfaction with their asthma symptom control and overall asthma care has been advocated.
The use of objective measures of asthma control and satisfaction may be especially important in the elderly as the perception of symptoms may be impaired with advancing age. In addition, many elderly patients unconsciously accommodate to their symptoms or assume that the symptoms are a function of the aging process itself. As the number of unscheduled ambulatory visits, emergency visits and hospitalizations are high in elderly asthmatics(164;165), and quality of life scores are low in elderly patients with persistent asthma when compared to those with mild asthma or no asthma at all(5). Careful assessment of asthma control is essential in this age group. Despite severe symptoms and physiologic impairment, most elderly patients with asthma can lead active productive lives if their asthma is appropriately managed. In fact, when elderly patients with severe or difficult to treat asthma have been identified by physician assessment, they appear to do better than younger patients. In the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study, despite lower lung function, older asthmatics (mean age 72 years) had lower rates of unscheduled office visits, emergency department visits, and corticosteroid bursts(81). Patients reported in this TENOR study received more aggressive care that younger adults including higher use of inhaled and oral corticosteroids and this undoubtedly had an impact on outcomes.
The tools to measure asthma outcomes include questionnaires and other self-report tools such as diaries, and standardized medical history forms. Standardized questionnaires that assess asthma impairment include the Asthma Control Test(166;167), The Asthma Control Questionnaire(168;169), The Asthma Therapy Assessment Questionnaire(170;171) as well as others(172–175).
To assess the quality of life of asthmatic patients there are many tools available to clinicians(176–179) (180–183). Unfortunately, these psychometric instruments that claim to measure the same outcomes may give disparate results and none have been targeted for the elderly. In general results that measure several domains are more accurate when composite score is derived rather than when sub-scores of specific domains are compared. Medical, administrative, and pharmacy records have also been used, especially to study larger asthma populations; they have proven useful for the assessment of an individual's change over time and to measure group differences. Clinical trials of asthma therapy, and educational, self-management, and health services interventions have used psychometric instruments to assess elderly patients with asthma. In most of these studies, however the majority of subjects are younger patients. There are no studies that have specifically determined the reliability and validity of these instruments in elderly persons. This is true of patient satisfaction measures that have been used to assess asthma care(184–186). This is much needed since using lung function testing to measure outcomes has potential limitations in this age group. There are difficulties in defining normal predicted values at a very advanced age and many patients with physical or cognitive impairment cannot reliably perform these tests. It is hopeful that newer biomarkers of lung inflammation have a particular role to play in assessment of asthma control in the elderly.
A major goal of geriatric and gerontology research is to reduce decline in cognitive and physical function and prevent disability among older adults. Accordingly, many functional status measures have been developed and used to understand the disabling process as well as to evaluate interventions to prevent functional decline. To investigate the functional consequences of asthma in older adults and to understand the pathway from asthma to disability, it is useful to identify instruments that measure functional limitations and disability. Functional limitations are restrictions in performing basic physical and mental actions at the whole person level (e.g., walking or climbing stairs); whereas, disability refers to limitations or difficulty in performing socially defined roles or tasks of everyday living in a given environmental context (e.g., grocery shopping or bathing)(187;188). Both self-reported and objective measures can be used to measure these different stages of disablement(189).
Self-reported measures can provide an indication of how well an individual is functioning in daily life and provide an assessment of care needs. These measures incorporate self-perception of function and can assess adaptations made to compensate for decrements in function(190). For disability assessment, self-reported difficulty or inability to perform basic Activities of Daily Living (ADL) is commonly used. For example, a composite score of 8 ADL items has been used as an outcome to evaluate the efficacy of a program to prevent functional decline in frail, older adults(191). Other composite scores assessing difficulty in ambulation, stair climbing, transferring, upper extremity function and basic and instrumental ADLs have been developed(192). These comprehensive instruments of function and disability are amenable to computer adaptive testing(193).
Several objective measures of physical performance are used in studies of older adults and in disease-specific patient populations. Tests of physical performance eliminate subjective, attitudinal differences in patient's reporting of physical function limitations. They have the advantage of providing an objective measure for comparisons across populations(194). These tests are sensitive to change over time and can detect decrements in function that may not be observed with self-reported instruments. Many studies in older adults have used physical performance tests as predictors of adverse health events as well as outcomes.
For example, the Short Physical Performance Battery (SPPB), which consists of timed balance, walking, and chair rise tasks, is a powerful predictor of disability, nursing home admission, and mortality(195;196). The SPPB was also used as a screening instrument to identify functionally limited older adults and as an outcome in a randomized, controlled trial of exercise(197). Increasingly, objective measures of physical function are used to summarize the impact of total disease burden, including sub clinical conditions and impairments, and to identify physiologic reserve that might help some older adults cope with disease burden. Clinically meaningful differences have been established for commonly used performance measures(198).
The goals of asthma therapy in elderly patients are not different from those for younger asthmatics(96). They are to treat acute symptoms, prevent chronic symptoms, decrease emergency department visits and hospitalizations, preserve normal activity level, and optimize pulmonary function with minimal adverse effect from medications(163;199) (200). Optimal management should also focus on improving health status (quality of life) in these patients, which is often complicated by depressive symptoms and side-effects from the drugs commonly used for asthma (201). Unlike many younger adults who may require no medication or just as needed beta agonist therapy for occasional symptoms, most older asthmatics need continuous treatment programs to control their disease. At a time when memory loss is common and financial resources are often limited, many older patients require complicated and frequent dosing with multiple expensive drugs. Unfortunately, this has led to a significant rate of noncompliance among the elderly population in general(45). Gender, socioeconomic factors, educational level, marital status, and severity of disease do not seem to be good predictors of compliance in elderly asthmatics. In summary, there are many challenges in the treatment of asthma in the elderly, which include a greater propensity to experience adverse events from medication use as well as potential drug interactions with medications used for the treatment of co-morbidities(4;96). Thus, it is particularly important to treat any disease in the elderly, including asthma, with a minimum of therapy while attaining maximum efficacy. In order to achieve this balance, a thorough understanding is required regarding which medications will be most effective in the treatment of asthma in the elderly. Since many current therapeutic options, and those in development for asthma, focus on specific inflammatory cells and mediators, any age-related changes in the airway inflammatory milieu will likely impact their therapeutic efficacy. Therefore, a rigorous characterization of age-related changes in airway inflammation will facilitate the management of asthma in the elderly.
Therapeutic approach to asthma in elderly patients does not differ from what is recommended for young patients. Statements on standard of care for treating asthma have been published by the National Institutes of Health and are widely used as guidelines(163;199). Treatment protocols use step-care pharmacologic therapy based on the intensity of asthma symptoms and the clinical response to these interventions. As symptoms and lung function worsens, step-up or add-on therapy, is given. As symptoms improve therapy can be “stepped down”. In this age group, special attention should also be given to the potential adverse effects of commonly used medications. Corticosteroids are capable of reducing airway inflammation and, thereby, improving lung function, decreasing bronchial hyperreactivity, reducing symptoms and improving the overall quality of life. Oral corticosteroids should be avoided if possible as they place the patient at risk for bone fracture and increased likelihood of cataracts, muscle weakness, back pain, bruising, and oral candidiasis(202). Many studies have shown that inhaled corticosteroids are safe and effective treatment for persistent asthma, but none have specifically targeted the elderly population. Long-term use of inhaled corticosteroids has been associated with a good safety profile but higher doses of inhaled steroids, for example greater than 1000 mcg per day, are capable of causing hypothalamic-pituitary-adrenal (HPA) axis suppression. Local adverse effects such as hoarseness, dysphonia, cough, and oral candidiasis do occur, but can usually be avoided by the use of a spacer or holding chamber with the metered dose inhaler and by rinsing the mouth after each use. Despite the pivotal role of inhaled corticosteroids in asthma, many elderly patients are undertreated with this group of medications(5;203).
Leukotriene-modifying agents (LTMs) are also asthma controllers. These agents have been shown to be effective in preventing allergen-induced asthma, exercise-induced asthma and aspirin-induced bronchospasm. Studies on their use in the elderly are limited. When compared to LTMs low-dose inhaled corticosteroids have favored the latter. The LTMs may also reduce asthma exacerbation rates and the need for steroid bursts. The LTMs are generally very safe(66;204).
Beta adrenergic agents are important medications in the acute and chronic management of asthma. Elderly patients with asthma may be less responsive to certain bronchodilators compared to younger patients(73;138).
Inhaled short-acting beta2 adrenergic agonists are the treatment of choice for the acute exacerbation of asthma symptoms. Despite the minimal systemic absorption seen with these agents, slight tachycardia may be observed. This is presumably due to vasodilatation, which results from the stimulation of beta2 receptors in vascular smooth muscle. Tremor may also occur and is especially troublesome in the geriatric patient. Tremor is thought to be caused by stimulation of beta2 receptors in skeletal muscle. In general, they have been proven to be safe and effective in all age groups(205). However beta agonists can cause: 1) a dose dependent drop in serum potassium and 2) a dose dependent increase in the QT interval on the electrocardiogram. Since sudden death from ventricular arrhythmia can be caused by both of these mechanisms as well as be a complication of ischemic heart disease, the use of beta-agonists in the elderly should be closely monitored. Short-acting beta2 – agonists should be used for rescue of symptoms, while long acting agents should be used as maintenance medications only as add-on to inhaled corticosteroids and never as stand- alone agents.
Anticholinergics such as inhaled ipratropium, a short-acting bronchodilator, and tiotropium, a bronchodilator with 24-hour action, have an excellent safety profile in the elderly. They should be considered when additional bronchodilator therapy is necessary; however, their role in long-term maintenance of asthma in the elderly has not been established.
Theophylline is an effective bronchodilator and has some anti-inflammatory properties. However, its use has been greatly reduced over the past decade due to safety concerns, especially in the elderly. The narrow therapeutic range of theophylline, frequency of concomitant illnesses that alter theophylline kinetics, and many drug interactions that affect the clearance of theophylline, make it essential to closely monitor the blood theophylline level in older asthmatics. Theophylline toxicity can cause seizures and cardiac arrhythmias such as atrial fibrillation, supraventricular tachycardia, ventricular ectopy and ventricular tachycardia. The most common cause for theophylline toxicity is a self-administered increase in medication.
Measures should be taken to avoid triggers that can cause worsening of symptoms. As with asthma at any age, education concerning avoidance of aggravating factors that can lead to severe bronchospasm is very useful. Although aeroallergens are less important in provoking symptoms in the elderly than young subjects, a program implementing environmental control measures, such as avoiding or minimizing aeroallergen exposure, should be instituted in patients with documented sensitivity to specific allergens. However, such programs may not be always successful, especially because life style changes in the elderly population may be difficult.
The most important provocative factors include viral respiratory infections, irritants such as cigarette smoke, paints, varnish, and household aerosols. Pharmacologic agents that are often prescribed for concomitant illnesses (ischemic heart disease, hypertension) such as beta adrenoreceptor antagonists (beta-blockers) can also provoke bronchospasm(206). This includes both non-cardioselective agents (propranolol, pindolol, and timolol) and to a lesser extent cardioselective agents (metoprolol and acebutolol). Topical beta-blockers are also widely used in the elderly to reduce intraoccular pressure in wide-angle glaucoma. With such treatment, sufficient systemic absorption may occur to cause fatal status asthmaticus(207). The severity of beta blocker-induced bronchoconstriction correlates with the severity of underlying airflow obstruction and the degree of bronchial reactivity and may be reduced by the use of a cardioselective topical beta blocking agent such as betaxolol(208). Aspirin, and nonsteroidal antiinflammatory agents may precipitate acute bronchospasm in certain asthmatics and angiotensin-converting enzyme inhibitors may cause dry cough in some, worsening the symptoms of asthma. Gastroesophageal reflux disease should also be considered as a cause of worsening asthma symptoms.
The complexity of prescription regimen (number and frequency of medications), coupled with the memory loss and cognitive dysfunction that may be present in this group of patients, contribute partially to poor compliance with therapy(4;96).
Patient education is an effective tool and should be an integral part in the management of asthma(209). Active participation by a patient and family members in monitoring lung function, avoidance of provocative agents, and decisions regarding medications provide asthma management skills that give that patient the confidence to control their own disease. Mastering the technique of inhaled medication delivery device is a challenging problem in elderly patients, and the great majority of elderly patients are unable to properly use the MDI, even after proper instruction(210–213). The use of dry powder devices, although simpler to use, require the generation of an adequate inspiratory flow which may be sub-optimal in frail patients and those with severe airway obstruction. In such situations, the use of spacer devices or nebulizers may be beneficial. Patients should recognize the rationale behind using the different medications, the correct way to use them, and their side effects and polypharmacy should also be avoided. Asthma in the elderly can be effectively managed and despite severe symptoms and physiologic impairment, most patients can lead active productive lives.
A demographic study of 380 low income elderly in Chicago found that 26 individuals (10%) without a previous diagnosis or asthma or emphysema had symptoms compatible with obstructive lung disease(214). Of subjects with a previous diagnosis, only 18% were compliant with medications and this was largely due to cost of medications. In addition, health care utilization was high in this population. Telephone intervention offers a simple option in the management of elderly patients with asthma. It has been shown that asthma care by telephone triage of adult asthmatics can lead to a higher percentage of asthma patients being reviewed at less cost per patient and without loss of asthma control when compared to usual routine care in the outpatient clinic(215). However, it has not been determined if such an intervention could improve asthma care specifically in people aged 65 years or older. The following study was designed to evaluate this question. Fifty-two elderly subjects with asthma that used their rescue inhalers more than twice a week and had at least 1 emergency department (ED) or urgent care visit in the previous year were randomized to an intervention or control group(216). All subjects received 2 phone calls over a 12-month period. The intervention group received an asthma-specific questionnaire and the control group received a general health questionnaire. Medication use and health care utilization were evaluated at the beginning and end of a 12-month period. The study was completed by 23 control and 25 intervention subjects. Baseline data were similar in both groups. After 12 months, 72% (n=18) of the intervention group was on an inhaled corticosteroid compared to 40% (n=10) of the control group. The intervention group had fewer ED visits when compared to the control group. Sixty-four percent (n=16) of the intervention group had an asthma action plan compared to 26% (n=6) in the control group. This study provides evidence that that using a simple telephone questionnaire can successfully improve asthma care in the elderly. By empowering the elderly with the appropriate knowledge regarding their asthma, an appropriate discussion about their asthma care can be initiated with their primary care physicians.
While pulmonary rehabilitation is recommended as standard of care for patients with COPD, there are only a few studies that evaluate the benefit of rehab for asthmatics and none of these consider elderly asthmatics. One study looked at the effects of a 10-week outpatient rehab program for 58 asthmatics after 3 years(217–219). They found that 39 of 58 subjects continued to exercise regularly all 3 years, there was a decreased number of ER visits and decrease in asthma symptoms. Further studies are needed to assess empowerment strategies for elderly patients with asthma as well as the potential benefits of pulmonary rehab on morbidity and mortality.
Asthma pathogenesis is complex, and incompletely understood. Research into the pathophysiological mechanisms is made more difficult by multiple factors including the heterogeneity of the disease itself, variable presentations in different stages of life, and lack of highly relevant animal models(220–224). In the last decade, increasing interest in asthma in the elderly has triggered more intensive investigation in both human and animal systems, utilizing ever more sophisticated immunologic methodologies.
Early investigation, utilizing rats, revealed lack of total and allergen-specific IgE in response to ovalbumin (OVA)(225). This was born out by several later in-vivo studies(226–228). IgG subset analysis (IgG1 vs IgG2) provided further support for this phenomenon. IgG1, correlating in mouse to a Th2 response (vs IgG2 –Th1) was shown to follow a similar pattern(227;228). Recent studies(226–228) of cytokine profiles in aged rodents, compared to young controls, enhanced the paradigm that age resulted in less robust Th2 cytokines, particularly for IL-4, IL-5, and IL-13, in favor of Th1 gene and protein expression(227;228). This pattern was not fully supported in a recent chronic asthma mouse model(229) wherein IL-5 was greater in aged sensitized mice, making the picture more complex. IFN-γ, a key Th1 cytokine, has been consistently over-expressed in aged vs young rodents(226–229).
Eosinophilia, considered a key component of (allergic) asthma, was more pronounced in younger vs older animals (bronchoalveolar lavage fluid (BALF) and/or lung tissue) following most sensitization paradigms(226–228;230), but not all(229). Molecular genetics and T-cell subset analysis has allowed further insight into possible mechanisms underlying the waning Th2 response observed in most models(227–229). Specifically, elderly mice appear to have more memory T-cells, less activated CD4+ Th2 cells, and less activated monocytes(227;228). Resident goblet cells also appear to express upregulation of mucin and mucin gene expression(229). A key to the impaired Th2 response was recently found in the GATA3 pathway(228). Elderly mice fail to phosphorylate components of the ERK MAPK pathway, resulting in lack of downstream signaling with GATA3, with subsequent impairment of promoter regions for key Th2 cytokines, including IL-4. This could be an over-arching explanation for many findings in the elderly asthmatic, including less IgE (IL-4 and IL-13 needed for opening switch regions for IgE production), IL-4 and IL-13 are highly associated with airway hyperreactivity (AHR), and IL-5 is associated with eosinophil activation, survival, and to a lesser extent, trafficking.
Finally, AHR has been universally found to be greater in young vs aged animals(226–229;231). The mechanisms may be complex, including both an altered key cytokine milieu, and alterations in muscle function at the muscarinic receptor level(231–233).
Research into the pathogenesis of asthma in recent years has led to the discovery of a number of novel, potentially important targets for the development of new treatment options. Much of this research has focused on Th2 lymphocyte-driven processes underlying allergic asthma and its characteristic eosinophilic airway inflammation. Abundant information supporting this research has been derived from bronchial biopsy and bronchoalveolar lavage studies largely carried out in a young adult population. It is recognized, however, that the role of allergy and allergic triggers in asthma diminishes with age(69;234). In addition, late onset asthma is often less reversible, more severe, and frequently occurs in response to a viral respiratory infection(153). A distinct asthma phenotype characterized by normal airway eosinophil numbers has been described(235). Moreover, normal airway eosinophilia may also be associated with abnormal sputum neutrophilia(236;237). Recent studies have shown that neutrophilic asthma may be associated with activation of innate immune pathways in contrast to the adaptive immune response associated with Th2-mediated allergic asthma(238). Thus, alternative immune pathways involving NKT or Th17 lymphocyte subtypes have been hypothesized as being potentially important in the pathogenesis of asthma, particularly in adult onset asthma(239;240). Just as the discovery of Th2-related pathways has led to important leads in drug discovery for allergic asthma, further clinical research into these alternative pathways should be carried out with the goal of identifying new and exciting targets for future drug discovery. This research should focus not only on the discovery of new molecular targets, but also on the identification of noninvasive biomarkers that will help predict the success of any new therapy in an individual patient.
Asthma is an important disease in the older adult affecting 7% of the population over age 65, which is understudied and frequently under diagnosed. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. This workshop explored and brought together many disciplines to further the understanding of our current understanding, gaps in knowledge and future areas of research and education. Table 1 lists specific areas in need of research and study.
The authors thank the National Institute on Aging (NIA) for recognizing the need for this workshop, especially Susan Nayfield, MD, who convened the workshop and provided tremendous support in moving this research field forward, Evan Hadley, MD, the Director of the Division of Geriatrics and Clinical Gerontology, and Basil Eldadah, MD, who continued the work of Dr. Nayfield and contributed valuable advice and encouragement to the authors in completing these proceedings.
Monroe James King, D.O. (Chair), Nicola A. Hanania, M.D., M.S. (Co-chair), Sidney S. Braman, M.D., Carol Saltoun M.D., Susan G. Nayfield, M.D., MSc. and Robert A Wise, M.D.
Alexander Auais, MD, Cynthia Boyd, MD, MPH, Stuart Brooks, MD, Ellen Brown, Carlos Camargo, MD, DrPH, Jerome Dempsey, PhD, Gang Dong, MD, PhD, Basil Eldadah, MD, PhD, Paul Enright, MD, William B. Ershler, MD, Ann Regina Falsey, MD, Carlos A. Vaz Fragoso, MD, James E. Fish, MD, Paul Garbe, DVM, MPH, Peter J. Gergen, MD, MPH, Lydia Gilbert-McClain, MD, Ethan A. Halm, MD, MPH, Robert G. Hamilton, PhD, Evan Handley, MD, Karen Huss, PhD, Charles G. Irvin, PhD, James Kiley, MD, Dennis K. Ledford, MD, Charlene Levine, John J. Lima, PharmD, Sameer Mathur, MD, PhD, Jeanne Moorman, MS, Enid R. Neptune, MD, Amy Pastva, PT, PhD, Kushang Patel, PhD, Katherine Pruitt, Joe W. Ramsdell, MD, Charles Reed, MD (Keynote speaker), Theodore Reiss, MD, Linda Rogers, MD, Sergei Romashkan, MD, Mark Sands, MD, David A. Stempel, MD, Virginia Taggart, MS, Alkis Togias, MD, Michael L. Terrin, MD, CM, MPH, Ying Tian, MD, PhD, Sandra R. Wilson, PhD, Barbara P. Yawn, MD, MSc. Stephen Wasserman, MD
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