Drugs Aging (2017) 34:157–162

DOI 10.1007/s40266-017-0437-y

THERAPY IN PRACTICE

Late-Onset Asthma: A Diagnostic and Management Challenge

Charlotte Suppli Ulrik1,2

Published online: 6 February 2017

Ó Springer International Publishing Switzerland 2017

Abstract Late-onset asthma is common, associated with optimally treated, the latter not least because elderly
poor outcome, underdiagnosed and undertreated, possibly patients are excluded from most randomized controlled
due to the modifying effect of ageing on disease expres- trials. Future studies should focus on the development of
sion. Although the diagnostic work-up in elderly individ- evidence-based guidelines for diagnosis and the pharma-
uals suspected of having asthma follows the same steps as cological therapy of asthma in the elderly, including late-
in younger individuals (case history and spirometry), it is onset asthma.
important to acknowledge that elderly individuals are
likely to have diminished bronchodilator reversibility and
some degree of fixed airflow obstruction. Elderly individ-
Key Points
uals, therefore, often require further objective tests,
including bronchial challenge testing, to objectively con-
Diagnosing new-onset asthma in the elderly is a
firm asthma. If necessary, a trial of oral or inhaled corti-
challenge.
costeroid might be necessary. Asthma can be diagnosed
when increased airflow variability is identified in a symp- The diagnostic procedures in elderly patients with
tomatic patient, and if the patient does not have a history of possible asthma should acknowledge the impact of
exposure, primarily smoking, known to cause chronic concomitant diseases.
obstructive pulmonary disease, the diagnosis is asthma Management of late-onset asthma follows
even if the patient does not have fully reversible airflow international guidelines, although the evidence has
obstruction. Pharmacological therapy in patients with late- been obtained largely from studies of non-elderly
onset asthma follows international guidelines, including patients.
treatment with the lowest effective dose of inhaled corti-
costeroid to minimize the risk of systemic effects. How- Diagnostic algorithms and evidence-based
ever, most recommendations are based on extrapolation management guidelines are needed for patients with
from findings in younger patients. Comorbidities are very late-onset asthma.
common in patients with late-onset asthma and need to be
taken into account in the management of the disease. In
conclusion, late-onset asthma is poorly recognized and sub-
1 Introduction

& Charlotte Suppli Ulrik Previous studies of the prevalence of asthma among adults
[email protected] have shown considerable differences between countries,
1
Department of Respiratory Medicine, Hvidovre Hospital, with estimates up to 16% in young adults and up to 10% in
2650 Hvidovre, Denmark adults over 65 years [1, 2]. The trend of enhanced long-
2
Institute of Clinical Medicine, University of Copenhagen, evity worldwide means that the number of older people
Copenhagen, Denmark with asthma will continue to rise for decades to come, and,
158 C. S. Ulrik

furthermore, children from the asthma epidemic in the 2 Definitions

1980s are growing older and will add substantially to the
number of older adults with asthma [3, 4]. The term ‘late-onset asthma’ refers to a person with onset
In spite of an increase in the proportion of elderly of asthma-like symptoms who is aged 60 years or older,
individuals presenting with symptoms suggesting a diag- defined on the basis of chronological age.
nosis of asthma [5], asthma in the elderly remains under- or Asthma is regarded as a disease characterized by vari-
misdiagnosed [6]. This is probably mainly due to the able airflow limitation leading to episodic symptoms of
erroneous belief that asthma is a disease with childhood cough, wheeze and dyspnoea, with the main therapeutic
onset [7], and, therefore, asthma symptoms occurring at targets being airway inflammation and airway wall
older ages may be attributed to other diseases, including remodelling–.
chronic obstructive pulmonary disease (COPD). Further- The clinical diagnosis of asthma requires objective
more, recognizing age of onset in elderly patients with assessment of lung function, preferably spirometry, and
asthma symptoms is very important as it may allow health demonstration of variability by bronchodilator or corti-
professionals to distinguish between truly late-onset dis- costeroid reversibility, airway hyperresponsiveness, e.g. to
ease and relapsing disease, as long-standing asthma inhaled mannitol, or increased diurnal variability in lung
recently has been shown to differ from late-onset asthma function, e.g. in peak expiratory flow rate.
with regard to clinical and physiological characteristics, as Chronic obstructive pulmonary disease (COPD) is
well as outcome [8]. regarded as a disease characterized by chronic airflow
Unfortunately, advanced age is an exclusion criterion in limitation caused by exposure to noxious particles or gas-
the vast majority of randomized controlled trials (RCTs), ses leading to symptoms of cough, sputum, dyspnoea and
and, therefore, our knowledge of asthma in the elderly with exercise limitation.
regard to pharmacological therapy is limited. The frequent Asthma–COPD overlap refers to patients with co-ex-
occurrence of comorbidities in elderly patients with asthma isting features of asthma, e.g. bronchodilator reversibility,
also contributes to exclusion of this subgroup of patients and COPD, with the latter including chronic airflow limi-
from RCTs. In line with this, it has previously been shown tation and relevant exposure, e.g. smoking.
that asthma patients enrolled in RCTs are not representa-
tive of real-life patients [9]. The consequence is that elderly
patients with asthma are very likely to receive pharmaco- 3 Diagnosing Late-Onset Asthma
logical therapy that has not been tested in this subgroup.
Asthma is diagnosed on the basis of symptoms and
1.1 Aims and Definitions objective assessment of variable airflow obstruction irre-
spective of the age of the individual suspected to be suf-
The primary aims of this review are to provide an update fering the disease. However, underdiagnosis of asthma
on current knowledge of diagnostic challenges, including remains a problem, as up to half of elderly individuals with
the differentiation between asthma and COPD, and man- asthma are undiagnosed [2, 10].
agement strategies, including pharmacological therapy, in Elderly patients often exhibit atypical symptoms and
elderly patients presenting with symptoms suggesting a may also have altered perception of their symptoms, and
diagnosis of asthma. one of the crucial issues related to late-onset asthma is
In accordance with the Preferred Reporting Items for proper recognition of the disease. The question is, there-
Systematic Reviews and Meta-Analyses (PRISMA) fore, whether the traditional diagnostic algorithm can be
guidelines, MEDLINE and the Cochrane Library were applied in individuals with late-onset symptoms. On the
searched using the terms ‘asthma’ and/or ‘pathophysiol- other hand, it appears likely that underdiagnosis of late-
ogy’, ‘diagnosis’, ‘management’, ‘therapy’, ‘outcome’, onset asthma would be lower if objective assessment,
‘morbidity’ and ‘mortality’, in combination with including spirometry, were more widely used [11].
‘elderly’, ‘late-onset’, ‘aging’ or ‘older’. Publications Although spirometry seems to be effective for identi-
within the last 5 years from peer-reviewed journals in fying patients with late-onset severe asthma [3], it may be
English were largely selected, but high-quality and fre- difficult to obtain a conclusive diagnosis not least in cases
quently referenced older publications were also included. of mild and moderate asthma [12]. Furthermore, perform-
Reviews were only included, to a limited extent, to ing spirometry in the elderly may be difficult because of the
provide the reader with more detailed background relatively high prevalence of cognitive impairments.
information (which could not be more extensively However, previous studies have shown that most elderly
addressed in the present review). individuals are able to perform acceptable and reproducible
Late-Onset Asthma: A Diagnostic and Management Challenge 159

spirometries [13, 14], although health professionals may Some patients with late-onset asthma may also, due to age-
consider using forced expiratory volume in 6 s (FEV6) as a related structural changes, not have reversible airflow
surrogate for forced vital capacity (FVC), as the manoeuvre limitation. Furthermore, some patients with COPD,
requires less physical effort [15, 16], or a lower cut-off for although having fixed airflow limitation, do have some
the FEV1/FVC ratio [12]. degree of reversibility [25, 26].
The structural changes in the aging lung are associated Although atopy is more common among elderly indi-
with some degree of persistent airflow limitation, and the viduals with asthma compared with in age-matched indi-
interpretation of spirometric curves in the elderly may viduals without asthma, evaluation of atopy is likely not
therefore be challenging, not least in borderline cases. useful in differentiating between asthma and COPD, not
These structural changes also account for the loss of least because the absence of atopy clearly does not rule out
reversibility, and this means that a bronchodilator a diagnosis of asthma [27, 28].
reversibility test may not be useful for diagnosing late- Emphysema is not a feature of asthma, and diffusion
onset asthma [10, 17]. capacity for carbon monoxide should be normal and, by
The fraction of exhaled nitric oxide (FENO) is a marker that, support a diagnosis of asthma and not COPD [27]. As
of eosinophilic airway inflammation, and findings from a it might be difficult to obtain valid measures of diffusion
recent study by Godinho Netto et al. [18] suggest that FE- capacity in elderly individuals, adding low-dose chest
NO measurements might be helpful in the diagnosis of late- computed tomography to exclude emphysema to the
onset asthma. However, routine measurement of FENO diagnostic procedures is likely to be helpful [29, 30].
may not be clinically valuable in elderly patients with The clinical implication of these considerations is that
asthma, as some patients may have some degree of neu- an elderly individual with overall characteristics pointing at
trophilic airway inflammation related to tobacco exposure a diagnosis of asthma should be classified, and managed, as
or a non-eosinophilic phenotype [19–21]. a patient with asthma regardless of the presence of non-
Compared with younger individuals, it is, therefore, reversible airflow obstruction.
likely that elderly individuals require further objective
tests, including bronchial challenge testing, to objectively
confirm a diagnosis of asthma. Unfortunately, no studies 5 Management of Late-Onset Asthma
have been published so far addressing the use of bronchial
challenge testing for diagnosing asthma exclusively in Although recent Global Initiative for Asthma (GINA)
elderly individuals, although it has previously been shown guidelines have allocated a section for the management of
in a group of adults with suspected asthma referred to a asthma in elderly patients [3], the lack of clinical evidence
university hospital that direct, e.g. methacholine, and on the efficacy of therapeutic agents obtained from elderly
indirect, e.g. mannitol, challenge tests differ with regard to patients is a major challenge in the management of late-
specificity and sensitivity for the diagnosis [22]. onset asthma. Therapeutic decisions in patients with late-
In the diagnostic work-up in elderly patients suspected onset disease will, therefore, largely have to be based on
of having asthma, it may, therefore, be necessary to pro- clinical experience, illustrating the major gap between
ceed with a trial of oral or inhaled corticosteroids (ICS), current available evidence and real-world practice in
not least in patients with post-bronchodilator airflow patients with late-onset asthma.
obstruction. The best efficacy-to-safety ratio for many drugs used for
Asthma can be diagnosed when increased airflow vari- the treatment of asthma is obtained by drug delivery by the
ability is identified in a symptomatic patient, and if the inhaled route. However, inadequate inhaler device technique
patient does not have a history of exposure, primarily is a substantial problem that may lead to poor disease control
smoking, known to cause COPD, the diagnosis is asthma [31], not least in elderly patients [32]. Furthermore, inade-
even if the patient does not have fully reversible airflow quate inhaler technique has also been shown to be associated
obstruction. with cognitive impairment and reduced lung function [31].
However, after detailed specific instructions, which need to be
repeated, the majority of elderly patients with asthma can
4 Distinguishing Late-Onset Asthma from COPD acquire and retain adequate device technique.
Chronic airway inflammation is a key feature of the dis-
Unfortunately, smoking history is not a clear-cut feature to ease, and ICS is, therefore, also the cornerstone of pharma-
distinguish asthma from COPD, as a substantial proportion cotherapy in patients with late-onset asthma. Although not
of patients with asthma are current or ex-smokers [23, 24]. based on evidence from clinical trials, low-dose ICS is
The distinction between asthma and COPD should not considered to be effective and safe also in elderly patients
be based on the response to a short-acting bronchodilator. with asthma. High-dose ICS therapy is associated with
160 C. S. Ulrik

systemic effects [33] and, across age groups, is only rec- late-onset asthma. So far, only a few post hoc or pooled
ommended for up to 6 months, unless it has been clearly analyses of omalizumab therapy in elderly patients with
shown that better asthma control is achieved on high-dose severe allergic asthma have been published [44–46].
therapy [3]. This highlights the importance of treating with However, RCTs will be necessary to establish the clinical
the lowest effective dose of ICS in patients with late-onset efficacy and safety profile of biologic therapy in patients
asthma, not least to reduce the risk for osteoporosis. ICS with late-onset asthma.
therapy has been associated with a higher risk of pneumonia
in patients with COPD [34], but the question of pneumonia
risk in patients with late-onset asthma has not been addressed 6 Co-morbidities in Patients with Late-Onset
in prospective studies. Asthma
Fixed-combination therapy with ICS and a long-acting
b2-agonist (LABA) is recommended if patients with The patient with late-onset asthma is, almost by defini-
asthma do not achieve disease control on ICS alone, tion, characterized by comorbidity, and the concomitant
although in elderly patients, this is based on very limited number of diseases increases with age. Previously, it has
evidence [35]. Fixed-combination therapy, i.e. ICS and been shown that more than 50% of individuals 65? years
LABA in the same inhaler, is recommended based on a have at least three concomitant diseases [47]. Based on
post hoc analysis of the Salmeterol Multicenter Asthma data from the UK General Practice Research Database,
Research Trial (SMART) showing that the increased risk of Soriano et al. [48] reported that the pattern of comor-
poor outcome was only observed among participants who bidities in elderly patients with asthma resembles that of
were not on concomitant ICS at baseline [36] and reported COPD, with ischaemic heart diseases, cataract and
differences in adherence with ICS and LABA prescribed in osteoporosis being the most prevalent concomitant dis-
separate inhalers [37]. eases. In patients with late-onset asthma, concomitant
Add-on tiotropium to fixed-combination therapy with rhinitis, gastro-oesophageal reflux, ischaemic heart dis-
ICS and LABA in patients with poor asthma control has ease, arrhythmias, diabetes and osteoporosis should be
been shown to be effective [38], and may also be used in treated according to guidelines.
patients with late-onset asthma, although direct clinical Apart from cognitive impairment, depression and anxi-
evidence is lacking. However, in a post hoc analysis of data ety are very common in elderly patients with asthma.
from the same studies, Kerstjens et al. reported that the Recognition and treatment of depression and anxiety in
effect of tiotropium on asthma control is independent of patients with late-onset asthma is important, as depression
age and age at onset of asthma [39]. Further, re-assuring is associated with poor outcome, including higher exacer-
evidence with regard to treating elderly patients with long- bation rate and mortality [49, 50].
acting anti-muscarinic agents comes from the large Tio- Taking comorbidities into account in the manage-
tropium Safety and Performance in Respimat (TIOSPIR) ment of patients with late-onset asthma is of upmost
study of patients with COPD over the age of 40 years [40]. importance, as a high number of prescribed medications
Approximately 50% of the patients included in the study may worsen adherence with controller medication for
were 65? years, and the study did not reveal any major asthma and increase the risk of drug interactions and,
long-term safety concerns [40]. therefore, have a negative impact on efficacy, safety
In contrast to previous studies where a very limited and outcome.
clinical effect of adding a leukotriene modifier to ICS was
found in elderly patients with asthma [41], a recent
12-week study of 140 elderly patients (60? years) with 7 Conclusions
mild asthma revealed that add-on montelukast to low-dose
ICS had similar efficacy to that of doubling the dose of ICS Late-onset asthma is underdiagnosed, undertreated and
[42]. Furthermore, it has also been shown that adding a associated with poor outcome. Furthermore, only very
leukotriene to ICS can improve outcomes in elderly limited evidence is available to support therapeutic deci-
patients with severe asthma [43]. Further studies in elderly sions in patients with late-onset asthma, as this group of
patients with asthma are needed, but leukotriene modifiers patients have been excluded from the majority of con-
may be a good option in this group of patients, also because trolled clinical trials of asthma therapies, including bio-
of the safety profile and method of administration. logics. More research is clearly needed that focuses
Biologic therapy, e.g. treatment with omalizumab or specifically on this vulnerable, growing group of patients
mepolizumab, for patients with late-onset asthma may be with asthma, so that future diagnostic and therapeutic
an important step forward in the management of severe algorithms can become evidence based.
Late-Onset Asthma: A Diagnostic and Management Challenge 161

Compliance with Ethical Standards 16. Pedone C, Bellia V, Sorino C, Forastiere F, Pistelli R, Antonelli-
Incalzi R. Prognostic significance of surrogate measures for
Conflict of interest CSU has no conflict of interest in relation to this forced vital capacity in an elderly population. J Am Med Dir
manuscript. Assoc. 2010;11:598–604.
17. Battaglia S, Benfante A, Spatafora M, Scichilone N. Asthma
Funding No sources of funding were used to support the writing of in the elderly: a different disease? Breathe (Sheff). 2016;12:
this manuscript. 18–28.
18. Godinho Netto AC, Dos Reis TG, Matheus CF, Aarestrup BJ,
Aarestrup FM. Fraction of exhaled nitric oxide measurements in
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