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Expert Review of Clinical Immunology

ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: http://www.tandfonline.com/loi/ierm20

Asthma in the older adult: presentation,


considerations and clinical management

Salvatore Battaglia, Alida Benfante & Nicola Scichilone

To cite this article: Salvatore Battaglia, Alida Benfante & Nicola Scichilone (2015): Asthma
in the older adult: presentation, considerations and clinical management, Expert Review of
Clinical Immunology

To link to this article: http://dx.doi.org/10.1586/1744666X.2015.1087850

Published online: 10 Sep 2015.

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Review

Asthma in the older adult:


presentation, considerations
and clinical management
Expert Rev. Clin. Immunol. Early online, 1–12 (2015)
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Salvatore Battaglia, Asthma affects older adults to the same extent as children and adolescents. However, one is
Alida Benfante and led to imagine that asthma prevalence decreases with aging and becomes a rare entity in the
Nicola Scichilone* elderly. From a clinical perspective, this misconception has nontrivial consequences in that the
recognition of the disease is delayed and the treatment postponed. The overall management
Dipartimento Biomedico di Medicina
Interna e Specialistica (Di.Bi.MIS),
of asthma in the elderly population is also complicated by specific features that the disease
University of Palermo Palermo, Italy develops in the most advanced ages, and by the difficulties that the physician encounters
*Author for correspondence: when approaching the older asthmatic subjects. The current review article aims at describing
Tel.: +39 09 16 80 26 55 the specific clinical presentations of asthma in the elderly and highlights the gaps and pitfalls
Fax: +39 09 16 88 28 42
nicola.scichilone@unipa.it in the diagnostic and therapeutic approaches. Relevant issues with regard to the clinical
management of asthma in the elderly are also discussed.

KEYWORDS: aging . asthma . asthma diagnosis . asthma physiopathology . comorbidity . elderly

Asthma in older adults is a disease of increas- related to the aging process per se and shared
ing interest for both specialists and general with other pathological conditions, while
practitioners. Several review articles on the others are disease specific and may deserve spe-
topic have been published by our [1–3] and cial attention. On the basis of these considera-
other groups [4–10], with the attempt to pro- tions, the current review article will mostly
vide a clearer vision of the comprehensive focus on the potential gaps in the understand-
management of asthma in the most advanced ing of the pathophysiological mechanisms of
ages. One of the main concerns lies in the fact geriatric asthma and the issues associated with
that the respiratory system is particularly sus- the application of the diagnostic work-up and
ceptible to age-associated deterioration in lung the therapeutic management of this population
structure and function [11], resembling a condi- in daily clinical practice.
tion of emphysema, with enlarged air spaces
due to the degeneration of the elastic fibers Epidemiology of asthma in the elderly
around the alveolar duct, and a parallel Asthma has been historically envisioned as a
decrease in elastic recoil; since the latter is con- disease of younger ages, leading to the assump-
sidered a limiting factor for the maximum tion that the occurrence of respiratory symp-
decrease in airway caliber during bronchocon- toms in older ages are to be attributed to
striction [12], the age-associated alterations of conditions other than asthma, mainly chronic
the lung may result in enhanced airway obstructive pulmonary disease (COPD). The
response to spasmogens, thus influencing the assessment of the prevalence of asthma in the
characteristics of the asthmatic phenotype in older ages has been limited by the methods
this age range. However, the senile lung is used and the lack of universally accepted crite-
clearly different from the emphysematous ria for the diagnosis in this age group and is
lung, in that it lacks airway wall destruction complicated by the confounding influence of
and distal duct ectasia [11], as shown by com- multimorbidity and geriatric-associated health
puted tomography [13]. conditions. In addition, little information is
The main challenges for physicians who available on the rate of relapse after asthma
manage asthma in the geriatric age are sche- remission in later life. The overall incidence of
matically presented in TABLE 1: some aspects are asthma in the elderly is difficult to estimate

informahealthcare.com 10.1586/1744666X.2015.1087850  2015 Informa UK Ltd ISSN 1744-666X 1


Review Battaglia, Benfante & Scichilone

Table 1. Major issues of asthma in the advanced ages.


Area of Reason/comment Ref.
interest
Diagnosis Difficulties in diagnosis related to physiological changes in the respiratory system due to the normal ageing [3,4]
process
Difficulties in performing lung function test by elderly subjects [65]

Difficulties in differentiating asthma from chronic obstructive pulmonary diseases [34,36]

Differences in the clinical presentations of asthma due to ageing and/or long disease duration [22]

Differences in the prevalence of allergic asthma in the elderly [4,77]

General Impaired capacity of elderly in recognizing asthma symptoms (dyspnea) [97]


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management
Impaired capacity of elderly for self-management of asthma [98]

Therapy Difficulties in using devices for inhaled therapy by elderly [98]

Drugs/comorbidities interactions in the elderly [6,38,43]

because it may be affected by the recall bias that influences the in childhood, disappears in adult ages and relapses in geriatric
reliability of self-reported disease; elderly patients who report a ages (case B); asthma occurring in geriatric ages, but with
late onset (see below) of asthma may suffer from variable doubts on its real age of onset (for example because of recall
degrees of cognitive impairment, leading to difficulty in recall- bias) (case C); asthma that begins in adolescence (case D) or in
ing clinical events that occurred during childhood or adoles- adulthood (case E) and persists till older ages; and asthma truly
cence. Overall, the incidence of asthma has been demonstrated presenting for the first time in geriatric ages (after age of
to decrease slowly with increasing age [14]. In the Obstructive 65 years; case F). The latter is without any doubt ‘late-onset
Lung Disease in Northern Sweden (OLIN) study [15], the inci- asthma’ [22,23]; however, some studies reported as ‘late’ also
dence of asthma was estimated at 2.3/1000/yr. cases of asthma beginning in adulthood (the cutoff point of
Studies in the European and US populations confirm that 40 years is often used) [24–27], in adolescence (the cutoff point
asthma is common among elderly to the same extent of youn- of 12 years is often used) [26,28,29], and even at school age (com-
ger ages [16–18]. A 10-year longitudinal study showed that the pared with infancy/preschool) [30,31]. As previous stated, late-
incidence of asthma in the elderly was estimated at 2.3/ onset asthma may have important different characteristics when
1,000/yr [15]. An important source of information on the epide- compared with early-onset asthma. Almost 20 years ago,
miology of asthma in the elderly is the National Surveillance of Braman et al. [22] described the characteristics of asthmatic
Asthma program of the USA [19]: between the years 2001– patients who developed asthma after 65 years: those with late-
2010, older Americans (aged >65 years) appeared to have had onset asthma had a lower likelihood of previous allergic diseases
the largest increase in the prevalence of current asthma, from and a significantly lower degree of airflow obstruction in pre-
6.0 to 8.1% compared with the different (younger) age groups, and post-bronchodilator spirometry, although the patients with
which was accompanied by the highest rates of asthma hospi- early- and late-onset asthma were indistinguishable by symp-
talizations and deaths. A trend of higher mortality rates in the toms and medication requirements [22]. These initial observa-
oldest asthmatics has been confirmed by other studies [20,21]. tions were conducted on a very small sample (25 cases), and
unfortunately very few studies have addressed this topic in
Clinical presentation of asthma in the elderly recent years. Compared with early-onset, in late-onset asthma,
In approaching asthma in the elderly, the age of disease onset is better lung function and milder CT scan abnormalities (fre-
a hot topic for several reasons: first, when an older patient quency of emphysema, bronchial dilatation and bronchial wall
refers to having suffered from symptoms suggestive of asthma thickness) have also been confirmed [23,24,32]. However, some of
in childhood or adolescence the disease is easier to recognize in these investigations [24,32] included as ‘late’ asthma cases pre-
clinical practice; second, the age of onset (in geriatric age or sented in adulthood. Taken together, these observations seem
early in the life) may influence the clinical presentations when to imply that: asthma can start at any age; and elderly with
compared with the common features. These possibilities are long-standing asthma (early-onset) may show features of
often referred to as ‘early’ and ‘late’ onset asthma. However, chronic persistent airflow obstruction.
some confusion in terminology exists in the current literature. One of the relevant features of asthma in geriatric ages is the
What can eventually be defined as ‘late-onset’ asthma? As common coexistence with COPD. The rising importance of this
shown in FIGURE 1, it is possible to hypothesize at least six differ- presentation (in the past reported as ‘asthmatic bronchitis’) is
ent scenarios: asthma that starts in childhood and persists (with confirmed by a joint project of international GINA and
symptoms or therapy) till older ages (case A); asthma that starts GOLD recommendations, which inserted a dedicated chapter

doi: 10.1586/1744666X.2015.1087850 Expert Rev. Clin. Immunol.


Asthma in the older adult Review

to the ‘asthma–COPD overlap syndrome’


Early onset ? onset ? onset Late onset
in the 2014 and 2015 GINA docu-
ments [33]. The Italian Gene–Environ-
ment Interactions in Respiratory Diseases
(GEIRD) study [34] demonstrated that, in
the general population, the prevalence F
of the overlap of asthma and COPD
E
increases with age, being on average
1.6% in the 20- to 44-year-old subjects, D
2.1% in the 45- to 64-year-old and 4.5% C
in the 65- to 84-year-old age groups. It
was not surprising that subjects with the B
overlap syndrome had a statistically sig-
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A
nificantly higher frequency of respiratory
symptoms, functional limitation and hos- Childhood Adolescence Adulthood Geriatric
pitalization with respect to subjects with
Figure 1. Possible scenario describing the different age of onset in asthma. For
the diagnosis of asthma or COPD
details see text.
alone [34]. Although the asthma–COPD
overlap syndrome does exist in real life, it
should be emphasized that, in many cases, a net distinction literature identified several diseases as being relevant in the
between asthma and COPD is possible with an accurate clinical elderly, including depression [39,40] atrial fibrillation [41] and
history and appropriate lung function tests [35]. Nevertheless, congestive heart failure [42].
however, the proper diagnosis is often a challenge in daily clini- Interestingly, data from Soriano et al. [43] support the notion
cal practice: in these cases, aging per se, and the presence of dis- that the pattern of asthma comorbidities modifies with aging.
ability may lead to an incorrect diagnosis of COPD in pure The authors demonstrated that in elderly (>65 year) asthmatic
asthmatic patients [36], with possible harmful consequences on patients, the pattern of comorbidities in newly diagnosed asth-
the therapeutic decisions. Interestingly, health-related quality of matics in primary care was significantly different (compared
life might have different evolution with aging, when asthmatics with younger asthmatic patients) and resembled that observed
are compared with COPD patients [37]. In both diseases, the in COPD, with angina (3.5%), cataract (3.0%) and osteoporo-
health-related quality of life declines with aging; however, over sis (2.7%) being the most prevalent conditions.
a 5-year period of follow-up, the declining trend was observed Patients with inflammatory bowel diseases show increased
in up to 80% of the COPD individuals, and only in 30–54% risk for other immune-mediated diseases including asthma [44,45].
of the asthmatic patients [37]. A limitation of this study was However, data on elderly patients are scanty, and further stud-
that the two groups were not age matched, since the mean age ies are needed to verify whether the relationship between
was 68 and 58 years for COPD and asthmatic subjects, respec- inflammatory bowel diseases and asthma is affected by age.
tively. It is possible to speculate that the steeper decline Asthmatics with comorbid conditions, such as heartburn, sinus-
observed in COPD could be age related instead of disease itis, congestive heart failure, chronic bronchitis and emphy-
related. Therefore, larger studies with longer follow-up and sema, were more likely to be hospitalized [42]. As a
age-matched cases are needed to confirm these observations. consequence, the higher risk of hospitalization observed in
The comorbidities are a well-known challenge for physicians elderly asthmatics compared with younger patients seems to be
who manage geriatric patients. This is likely true for every dis- linked to the higher prevalence of risk factors for hospitaliza-
ease, and asthma is not an exception [38]. Theoretically, each tion [42]. As a consequence, the higher risk of hospitalization
aging-linked disease or highly prevalent disease could interfere observed in elderly asthmatics compared with younger patients
with asthma management in the elderly [6]. Cazzola et al. [38] seems to be linked to the higher prevalence of aging with other
described the impact of age on 16 chronic comorbidities (ische- risk factors that predict hospitalization, including more respira-
mic cardiopathy, myocardial infarction, cardiac arrhythmia, tory symptoms, worse general health, and limited education [42].
heart failure, hypertension, cerebrovascular disease, other heart With regard to the risk of hospitalization, interesting results
disease, pulmonary embolism, allergic rhinitis, rhinosinusitis, comes from a Korean retrospective study [46] aimed at assessing
diabetes, dyslipidemia, osteoporosis, psychiatric disorders, the association between the outpatient service used by the
depression and gastroesophageal reflux) in patients with asthma. elderly and health resource utilizations, including hospitaliza-
For all comorbidities, increasing age resulted in a progressive tion. The results demonstrated that, as the level of continuity
rise in prevalence (with the exception of allergic rhinitis that use of outpatient service decreased, emergency department visits
decreased), but changes in age did not increase the association and mean healthcare costs, as well as hospitalization,
with asthma [38]. Even if the association between asthma and increased [46]. Other comorbidities, such as atopic dermatitis or
comorbidities would not be stronger with aging, published eczema [47], atopy, rhinitis [48], gastroesophageal reflux, are

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Review Battaglia, Benfante & Scichilone

also related to decline in the generation


Asthma comorbidities in the elderly of naı̈ve cells [8,52], an accumulation of
memory T cells (shift from naı̈ve to
memory lymphocytes), a decline in T-cell
Sharing risk repertoire and B-cell functions [53,54]. It
factors; common Likely related to
pathways; direct
Likely related to
asthma treatment
was suggested that the actual mass of
aging T and B cells undergoes a 25% reduction
relation; related (side effects)
to asthma per se with aging. In addition, studies per-
formed in vitro showed that naı̈ve
Depression; cognitive Cataracts;
CD4 cells isolated from older humans
Rhinitis; GORD; impairment; have decreased responsiveness to activa-
osteoporosis;
IBD, metabolic cardiovascular,
syndrome
arrhythmias; diabetes tion through T-cell receptor pathways
arthritis, renal failure
and through different cytokines when
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compared with naı̈ve CD4 cells of young


Action:
Action: Evaluate during subjects. In aged animal models, it has
Action:
Treat to improve Assess before asthma asthma treatment to been shown that aging is also character-
asthma outcomes treatment to avoid reduce drug dosage ized by macrophage dysfunctions, consist-
drugs interaction or and prevent side ing of reduced expression of Toll-like
treatment failure effects
receptors, reduced secretion of cytokines
following activation and reduced phago-
cytic ability, according to parallel decreas-
Figure 2. Asthma comorbidities in the elderly grouped according to shared risk
factors, age and treatment. ing levels of macrophage-derived
GORD: Gastroesophageal reflux disease; IBD: Inflammatory bowel disease. chemokines [55,56]. Effect of aging on
monocyte and macrophage in humans is
controversial regarding their functional
common in younger asthmatics and are also present in elderly impairment. A study undertaken to investigate whether
asthmatics. In clinical practice, it could be useful to classify and increased numbers of neutrophils can be found in the bron-
distinguish the comorbidities according to the actions to be choalveolar lavage of old healthy subjects showed that neutro-
taken in handling them. A potential scenario is presented phils were significantly elevated in the oldest versus youngest
in FIGURE 2. groups, thus suggesting a low-grade inflammation in the air
spaces of older individuals [57,58]. In addition, the authors dem-
Considerations on asthma pathophysiology in the onstrated the occurrence of an altered inflammatory profile,
elderly including a significant rise in immunoglobulins, cytokines
As a general concept, asthma in this population is poorly (IL-6 and IL-8), neutrophil elastase, antiproteases, superoxide
assessed and undertreated, due to the paucity of studies specifi- anion and other byproducts of neutrophil activation.
cally designed to establish the proper management of asthma in One of the main concerns when managing older individuals
elderly patients, who are usually excluded from asthma clinical with suspected asthma is, how to diagnose airway obstruction
trials. We believe that the low level of knowledge of the patho- in the elderly [59]? Lung function assessment with spirometry is
physiology of asthma in the elderly is the main limiting factor recommended at any age, and it has been largely demonstrated
when managing the disease. that the majority of elderly patients may perform acceptable
Although it is accepted that aging cannot be regarded as a and reproducible tests in the adequate specialist setting [60].
disease, the changes in lung function and cells that character- The latest GINA international document [33] states that “the
ized aging result in reduced respiratory functional defense and FEV1/FVC ratio is normally greater than 0.75 to 0.80 . . . Any
increased susceptibility to stress factors and diseases [49]. In this values less than these suggest airflow limitation. Many spiro-
context, it is worth exploring whether the inflammatory disor- meters now include age-specific predicted values.” However,
der in elderly asthmatics differs from that of young asthmatics. this statement poses several concerns. At least two main issues
The immune system dysfunctions occurring with aging are are a matter of discussion: Is the FEV1/FVC ratio (per se,
termed immunosenescence [50] and affect both the innate and the at any age) reliable compared with the use of lower limit of
adaptive immunity. The most important clinical impact of normal in defining airway obstruction? Is the FEV1/FVC ratio
immunosenescence is an increased susceptibility to microbes, reliable in the elderly?
such as viral or bacterial airway infections. In older asthmatics The LLN is theoretically preferred because it limits the risk
and in children, viral respiratory infections are associated with of under or overdiagnosis of airway obstruction. Nowadays, the
worsening of asthma control [51]. Studies have suggested that LLN is electronically calculated by appropriate software and
sustained antigenic stress over a lifetime leads to a decline in therefore readily available. However, LLN values for elderly are
naı̈ve T cells in the thymic compartment and the periphery, scanty, although elderly-specific reference equations have been

doi: 10.1586/1744666X.2015.1087850 Expert Rev. Clin. Immunol.


Asthma in the older adult Review

developed [61–64]. In this contest, one of the largest studies aim- represent the chronic features of human allergic asthma. In fact,
ing at developing reference equations has been performed by while elderly asthmatics have been exposed to seasonal allergens
Quanjer et al. [65], who published the Global Lung Function for several decades and undergo intermittent exacerbations, aged
Initiative (GLI) multiethnic reference equations for spirometry animals are both sensitized and challenged at old age. For many
for subjects aged 3–95 years. However, the study by years, asthma in the elderly was depicted as nonatopic or intrin-
Quanjer et al. points out that “Caution is required when com- sic. In the past two decades, it has been shown that atopy is not
paring spirometric test results in those over 80 years with the uncommon in these populations. Several studies reported that
present GLI prediction equations.” Indeed, in this study allergy skin tests were positive in 8–12% of the general popula-
(including more than 74,000 subjects), Caucasian subjects aged tion of older adults [4,73]. In a systematic review, article that
80 years and over scored as low as 0.8 and 1.3% for men and aimed at assessing the impact of age on atopy [74], Scichilone
women, respectively. These percentages are even lower for the and colleagues found a decreasing prevalence of atopy with age
other ethnic groups: for instance, the reference sample only either in the general population samples or in population sam-
includes 10 African American elderly men >80 years. Under ples of healthy, that is, with no allergy-related symptoms,
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these conditions, it is plausible to hypothesize that LLN values humans. The authors pointed out that the evaluation of the
for the elderly would benefit by more robust data. Moreover, atopic status in the majority of the studies was performed with-
the use of FEV1/FVC fixed ratio versus LLN (at any age) has out discriminating between specific IgE levels and the response
been extensively debated [66–68], especially in the context of the to allergen skin prick test, thus limiting the conclusions on the
chronic obstructive pulmonary diseases. Finally, the experience prevalence of the allergic component in the elderly. In the
of our group [69] pointed out that the use of lower fixed FEV1/ SAPALDIA [75], the prevalence of allergen-specific IgE antibody
FVC ratios (0.67 in women and 0.65 in men) approach the concentrations, positive prick tests and allergic manifestations
LLN (fifth lower percentile). Perhaps, the issue is not the fixed decreased significantly by 23, 21 and 21%, respectively, with
ratio versus the LLN, rather the choice of an age-specific cutoff every 10-year increment in age. Similarly, in a population-based
point for the diagnosis of airway obstruction in the elderly. longitudinal study, Warm and coworkers [76] investigated the
This could especially apply in clinical practice, where functional prevalence of allergic sensitizations among adults in relation to
data are combined with medical history (symptoms, exposure aging over a 10-year period. The authors found low incidence
and comorbidities). (5%) and high remission (32%) rates during a 10-year period of
In the differential diagnosis of asthma in the elderly, the observation, explaining the decreasing prevalence of allergic sen-
assessment of airway hyper-responsiveness (AHR) could gener- sitizations with increasing age per se. These findings are in line
ate doubts. These issues have been reviewed elsewhere [70], and, with more recent observations from the GA2LEN survey [77],
in summary, the prevalence of AHR appears to increase with which clearly demonstrate that positive skin prick test for all
age. Probably, the distribution of AHR in the general popula- allergens is more common in younger adults than in older adults
tion shows a U-shaped form, being highest in children/ (age range 45–77 yr). In the Normative Aging Study [78],
adolescents and in the elderly [70]. Several factors have been subjects with documented AHR had higher rates of serum IgE
proposed as determinants of this enhanced reactivity, and pre- reactivity to cat allergen and mites when compared with age-
test reduced lung function and a history of smoking are the matched controls. It was hypothesized that the impact of indoor
main predictors of greater airway responsiveness. As a conse- allergens would be higher in the older individuals, who are sup-
quence, bronchoprovocation tests performed in elderly subjects posed to spend more time in the same environment compared
should be carefully interpreted. with younger adults. This is confirmed by another study con-
Little is known about the effect of asthma on lung function ducted in asthmatics by Rogers and coworkers [79], which
and structure in later life [71]. With the purpose of exploring reported that 60% of the asthmatics >65 years were sensitized to
this, Donohue et al. [72] demonstrated that patients with asthma at least one allergen, with the most prevalent detectable allergen-
onset at any age, including childhood or young adulthood, had specific IgE being to cockroach. In addition, the cockroach sen-
significantly lower lung function in later life than healthy con- sitization appeared to be correlated with more severe asthma.
trols. Moreover, smoker asthmatics had greater percentage of Obviously, increased specific IgE levels or positive skin prick
low attenuation area on CT scan than participants without test responses to allergens cannot be used interchangeably in
asthma. The strength of Donohue’s study [72] is the inclusion older individuals, because both components are variably affected
of 446 asthmatics and 2925 controls in a population-based by age-related factors, as well as by different designs and meth-
cohort of older adults (mean age 65 years) and the use of CT ods for estimation of sensitization, and this limits the conclu-
scan to investigate the lung structure, although the study was sions on the exact prevalence of the allergic component in the
not prospective. elderly populations and the comparison between studies on the
The issue of atopy in the elderly has always been a matter of topic. Interestingly, one explanation for the large variability in
debate. Studies were performed on animal models to address the prevalence of allergen sensitization in the elderly could lie in
age-related changes in the function of inflammatory cells and the age of asthma onset, in that, when asthma begins before the
the airway inflammation induced by allergen challenge, showing age of 40 years, an higher association with positive allergy tests
controversial findings. Animal models do not accurately is found as opposed to late onset asthma [22,78].

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Review Battaglia, Benfante & Scichilone

Obesity has been proposed as risk factor for asthma [80], modest and inconsistent associations with cognitive function in
Song et al. [81] explored this in the elderly population with older individuals with asthma [95]. To defend their results
focus on central adiposity and loss of appendicular skeletal against previous literature, the authors [95] propose that greater
muscle mass using abdomen computed tomography and dual- differences in cognitive performance may exist between older
energy X-ray absorptiometry. They demonstrated that asthma individuals with and without asthma than in older individuals
was more strongly associated with abdominal subcutaneous adi- with asthma with different levels of disease control.
posity compared with visceral adiposity and was inversely asso- A population-based study [96], characterized by a 25-year follow-
ciated with appendicular skeletal muscle mass among the up, supports the association between asthma and deterioration
Korean elderly population [81]. However, Song’s results should of cognitive performance: midlife COPD and asthma were asso-
be interpreted with caution: the inverse correlation with skeletal ciated with an almost twofold risk of clinically diagnosed mild
muscle mass is indeed a positive association with sarcopenia. cognitive impairment and dementia later in life. In this context,
This may suggest that the ‘true’ risk factor for asthma is under- promising results demonstrate that in older asthmatics, who
nutrition with muscle depletion instead of the obesity with receive proper asthma management is capable of improving
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abdominal subcutaneous fat deposition. Other findings from asthma control irrespective of lung function impairment.
USA [82] on asthmatics aged 6–76 years old demonstrated that Depression has been identified as a condition strongly associ-
age is an important effect modifier in the obesity–asthma rela- ated with poor asthma control and quality of life in the elderly
tionship in children, while it did not significantly impact lung with mean age of 73.3 years and mean duration of asthma
function decline with advancing age [82]. To further complicate diagnosis of 28.5 years [39]. Moreover, the same study demon-
this scenario, a prospective study with 13-year follow-up found strated that worse physical and mental status were correlated
a U-shaped association between the annual incidence of asthma with poorer asthma quality of life, and subjects who lived alone
onset and body mass index in the elderly men (not for the were more likely to have unscheduled visits [39]. Other data [40]
women) [83], thus supporting both underweight and obesity as also confirm that elderly (>60 years) asthmatics with depressive
risk factors for asthma. symptoms were more likely to report poor asthma control,
worse quality of life and poor adherence to therapy. Anxiety or
Clinical management depression is obviously associated with asthma also in younger
It has been demonstrated that the level of asthma control is asthmatics; however, there are evidences [97] that this association
poor in the elderly [84] even when they were considered by their could be stronger in the elderly probably due to the concomi-
general practitioners as mild asthmatics and treated with inhaled tant presence of other comorbidities. A recent study [41] dem-
steroids [85]. From a clinical perspective, it is possible to propose onstrated that asthma is associated with a 1.2-fold higher risk
a different phenotype according to the age of asthma onset. The of new-onset atrial fibrillation after adjusting for underlying
late-onset disease appears to be more severe and less atopic; risk factors (comorbidities and medication), suggesting that
interestingly, it has been associated with ‘aging’ b-2-adrenocep- asthma may play an important role in atrial fibrillation initia-
tor [86], which could account for a more ‘difficult to treat’ con- tion. Moreover, the current use of inhaled corticosteroids, oral
dition. Furthermore, the Severe Asthma Research Program corticosteroids and bronchodilators was associated with an
(SARP) study [87] found that late-onset asthma is strongly asso- increased risk of atrial fibrillation, especially for new users [41].
ciated with features of severe asthma, in association with the fre- These observations may apply to the elderly since the sample
quent occurrence of sinus disease. This was also confirmed by mean age was 71 years.
the GA2LEN study [88] in which a strong association between Atopy seems to affect the asthmatic phenotype in the elderly
late-onset asthma and chronic rhinosinusitis was described. Sev- population. The Epidemiology and Natural History of Asthma
eral different factors have been advocated to explain the lack of (TENOR) study [73] investigated the natural history of asthma
symptom control in elderly asthmatic patients. Among these, in older than in younger asthmatics affected by severe or diffi-
the poor recognition of symptoms with blunted perception of cult-to-treat asthma. Older asthmatics had lower total IgE levels,
dyspnea [89], unintentional nonadherence with inhalation ther- fewer positive skin prick tests and less concomitant allergic rhi-
apy [90,91], difficulties associated with cognitive impairment [92,93], nitis or atopic dermatitis. Elderly asthmatics underwent disease
depression [40], concomitant medications [94] and socioeconomic exacerbations due to triggers that differed from the common
problems [85]. Partially in contrast with these observations, inhalant allergens. It is plausible to speculate that the presence
recent studies demonstrated that nonrespiratory comorbid- of specific IgE against the common aeroallergens in the most
ities [94] and cognitive function [95] do not seem to have a direct advanced age, although lower than in younger asthmatics,
negative impact on asthma control. Although the presence of impacts the clinical presentation, likely because it increases the
comorbid conditions in older patients should not be associated susceptibility to viral infections and therefore the risk of exacer-
per se with worsened asthma control and/or increased disease bations and the chances of unstable asthma (FIGURE 3) [98]. Indeed,
severity, the results of the cited study [94] could have been influ- Heymann and coworkers showed a higher risk for asthma hospi-
enced by the setting (close follow-up in secondary asthma clin- talization when atopy and viral infections were combined [99].
ics). With regard to the cognitive impairment, some evidences Immunosenescence may affect the ability of older adults to clear
indicate that asthma control and airway obstruction have viruses efficiently, and thus greater and more prolonged

doi: 10.1586/1744666X.2015.1087850 Expert Rev. Clin. Immunol.


Asthma in the older adult Review

inflammation may result. Some authors [100–102] explored the


incidence of viral infection in adult asthmatics and demon-
strated infection rates of 10–29% using viral culture and serol- Atopy
ogy for diagnosis [102]. More recent studies showed higher
infection rates of 44–55% [100,101], with rhinoviruses being the
most frequently detected microorganism, using reverse tran-
scription polymerase chain reaction (RT-PCR).
It is unclear whether neutrophilia alters treatment response
and clinical outcomes in elderly asthmatics. In a recent
study [103], the authors hypothesized that, in older asthmatics,
eosinophilic airway inflammation is associated with AHR, Severity of asthma
while neutrophilic inflammation may be an important
determinant of airflow limitation and airway closure during
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bronchoconstriction. In a pilot study of young and older mild-


Age
to-moderate asthmatics [104], older subjects had lower in vivo
levels of leukotriene B4 (LTB4) and cysteinyl leukotrienes in Figure 3. Relationship between prevalence of atopy,
the sputum. Vignola and coworkers [105] compared two groups disease severity and aging.
of asthmatic subjects of different ages. Sputum neutrophil per-
centage was higher in the elderly than in the younger group;
both in young and elderly asthmatics, the percentage of neutro- investigations should allow to test whether exhaled NO may
phils was directly correlated with the duration of the disease. become a promising marker for asthma in the geriatric age.
However, the levels of both total and active elastase in the The clinical presentation obviously affects the pharmacologi-
elderly asthmatics did not differ from those of young asth- cal treatment in the most advanced ages. When smoking habit
matics, implying that age per se does not affect the production is present, smoke cessations should be pursued actively and
of elastase, and suggesting that an important variable in the aggressively. In addition, there is no real contraindication to
development of airway remodeling in both young and elderly specific immunotherapy in the elderly, especially when using
asthmatics is represented by the duration of the disease. the sublingual route of administration, which is safe. The phar-
In this scenario, an imperative unanswered question is macological treatment of asthma in the elderly is an arbitrary
whether a biomarker, or a combination of them, has been iden- extrapolation of what has been tested in young ages, given that
tified to follow the disease and tailor the treatment in the elderly. age has always represented an exclusion criterion for eligibility
A prerequisite is that asthma has to be clearly distinguished from to clinical trials. However, there has never been any warning to
COPD. Fabbri et al. [106] showed that asthma in the elderly the application of inhaled pharmacological treatment that is reg-
maintains a different pathology compared with COPD, even in ularly used in the young asthmatics on geriatric populations.
the presence of nonreversible airway obstruction. According to The elderly asthmatics are at higher risk of side effects due to
this finding, Di Lorenzo et al. [107] found that, despite similar the concomitant extra-pulmonary diseases and the prescription
fixed airflow obstruction, elderly patients with asthma maintain of multiple drugs. From a clinical perspective, the association
a distinct inflammatory pattern in the induced sputum and the between asthma and cataracts is worth exploring, given the high
peripheral blood compared with patients with COPD. Several prevalence of cataracts in geriatric subjects. The interaction
studies [108] described an increase in sputum neutrophils and a between asthma and cataracts may theoretically have several rea-
decrease in macrophages and lymphocytes in elderly asthmatics, sons: on the one hand, asthma treatment (i.e., inhaled cortico-
regardless of the severity of the disease. Therefore, the exact steroids [110]) has been proposed as a risk factor for developing
description of the inflammatory population in the airways of cataracts; on the other hand, the presence of asthma could be a
elderly asthmatics is yet to be attained and requires specifically risk factor for complication of cataract surgery treatment. With
designed studies that are devoid of confounding factors, such as regard to these possible concerns, literature data are reassuring.
the overlap asthma–COPD syndrome. Indeed, the risk of developing cataracts for users of inhaled cor-
Measurements of exhaled nitric oxide (NO) concentrations ticosteroids seems low [111,112] or derived from not robust
have been proposed as sensitive noninvasive marker of asthma data [113] and probably without a dose–response relation-
disease activity, reflecting airway eosinophilic inflammation. ship [114,115]. In summary, the benefits of therapy likely over-
Few data are available on the effects of age on NO levels in come potentials harms [116]. On the contrary, a significant
the expired air. Olin and coworkers [109], observed that age is increase in cataracts has been demonstrated with the use of oral
independently and positively associated with NO concentra- corticosteroids [117].
tions. In this study, the oldest group had a 40% higher NO Another clinical issue related to treatment for asthma in the
value when compared with the youngest group. When the geriatric population is represented by osteoporosis. A prospective
models were stratified according to gender, and the presence open cohort study from UK on a very large sample of subjects
or absence of asthma, similar results were found. Future aged 30–100 years identified asthma (along with other variables)

informahealthcare.com doi: 10.1586/1744666X.2015.1087850


Review Battaglia, Benfante & Scichilone

as risk factor for osteoporotic fractures [118,119]. This observation majority of treatment failure in the elderly, since they can influ-
is reinforced by other data on patients with mean age of 74 years, ence treatment adherence and the achievement of the outcomes.
showing an association between asthma and lower bone mineral There is room for research in this field: elderly are always hard to
density at the spine and hip and increased risk of vertebral and be enrolled in randomized clinical trials (RCTs); however, to
nonvertebral fractures [120]. However, these data [120] have several treat patients without scientific evidences is undoubtedly harder.
limitations because asthma and COPD were analyzed together, The importance of real-life studies is increasing, due to their
and patients using oral steroids were not separated from those value in overcoming clinical trial weaknesses.
using inhaled corticosteroids.
Older asthmatics may experience more adverse drug effects Five-year view
because of pharmacodynamic and pharmacokinetic changes, and Our group has recently shown that asthmatics enrolled in
particularly drug–drug and drug–disease interactions. Finally, RCTs are not fully representative of real-life patients [121]. This
physical and cognitive impairments may affect the adherence of becomes dramatic in elderly patients in whom the odds ratio
elderly patients to treatment strategies, thus affecting asthma to be excluded from RCTs can increase to 35 for asthmatics
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control. Taken together, these observations lead to the observa- aged 75–84 years compared with those aged 15–24 years [121].
tion that efforts should be implemented to help the physicians The presence of comorbidities plays a pivotal role in excluding
to properly recognize and treat asthma in the geriatric age. elderly asthmatics from RCTs. As a consequence, almost half
of elderly asthmatics are treated with drugs that have not been
Expert commentary tested in such populations. On this basis, we propose that in
In the past decade, the knowledge on asthma in the elderly has the near future, RCTs should be specifically designed with the
enormously expanded, and currently, it is well known that aim of expanding knowledge on pharmacological treatment of
asthma can start at any age, and that it does not ‘disappear’ in the elderly asthmatics. To this purpose, RCTs on unselected popu-
elderly. In diagnosing airway obstruction in the elderly, physi- lations (e.g., including elderly asthmatics with comorbidities)
cians must consider that the clinical presentation can be slightly are encouraged.
different. In this perspective, a fixed airway obstruction should
not always imply the presence of COPD, because ‘pure’ asthma Financial & competing interests disclosure
may also present these features. We firmly avoid the ‘temptation’ The authors have no relevant affiliations or financial involvement with
that each airflow limitation in the elderly is an indistinct mix of any organization or entity with a financial interest in or financial conflict
asthma and COPD with the harmful consequence that one ther- with the subject matter or materials discussed in the manuscript. This
apy fits all. Although asthma may coexist (overlap) with COPD, includes employment, consultancies, honoraria, stock ownership or options,
patients should be referred to specialists for an accurate func- expert testimony, grants or patents received or pending, or royalties.
tional diagnosis. Comorbidities probably account for the No writing assistance was utilized in the production of this manuscript.

Key issues
. Asthma can start at any age. The age of asthma onset may affect the clinical presentation of asthma in the elderly. Early onset asthma
is easier to recognize, when a well-documented history of asthma in childhood or adolescence is present. However, it may show fea-
tures of chronic persistent airflow obstruction.
. Asthma may coexist with chronic obstructive pulmonary disease (asthma–COPD overlap syndrome); in many cases, a clear distinction
between asthma and COPD is possible with an accurate clinical history and appropriate lung function tests. Nevertheless, the proper
diagnosis is often a challenge in daily clinical practice.
. Several comorbidities are associated with asthma in the elderly, and this association differs from that observed in younger patients.
. In clinical practice, physicians should treat comorbidities strictly correlated with asthma physiopathology (i.e., rhinitis or GORD), assess
comorbidities that may influence asthma outcomes (i.e., depression or cognitive impairment) and try to prevent comorbidities related to
drug-associated side effects (i.e., cataracts, arrhythmias or osteoporosis).
. The diagnosis of airway obstruction in the elderly can represent a challenge. The use of FEV1/FVC as a fixed ratio is suitable to define
the presence of airway obstruction in adults in clinical practice. In the elderly populations, the threshold value of FEV1/FVC should be
lowered from 0.70 (applied in adults) to 0.65 to avoid the risk of overdiagnoses. In this scenario, the use of lower limit of normal is to
be preferred.
. The prevalence of allergic sensitizations is lower in the most advanced ages due to the phenomenon of immunosenescence. However,
this component worsens the clinical manifestations of asthma and should be properly assessed and treated.
. Although obesity is a risk factor for asthma also in older adults, malnutrition (e.g., undernutrition) could play the most relevant role.
. Achieving asthma controls is often a difficult task in the elderly. Depression and cognitive impairment may play an important role and
need to be regularly checked and managed.

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Asthma in the older adult Review

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