Choosing wisely: practical considerations on treatment efficacy and safety of asthma in the elderly

The world population is ageing, and life expectancy (meaning the number of years an
individual can expect to live) is steadily increasing. Because of increased longevity,
the proportion of individuals aged 65 years and older (referred to as the elderly)
is growing worldwide. Given these demographic changes, the impact of asthma is expected
to rise in the next years. The management of asthma in the elderly follows international
guidelines that apply to all ages, although most recommendations are an arbitrary
extrapolation of what has been tested in younger subjects. In fact, age has always
represented an exclusion criterion for eligibility to clinical trials. Many specific
factors affect treatment of the elderly. They often undertake a number of medications
as they frequently suffer from different diseases and comorbidities. Polypharmacy
increases the risk of low adherence and of interactions between different drugs. Furthermore
elderly patients may present cognitive dysfunction that results in a decreased memory,
which in turn affects the compliance to the treatments. The changes in body composition
and metabolism that characterize aging process should also be carefully taken into
account. The pharmacological effect of systemic drugs may be affected by the reduced
activity of kidney and liver and by the decrease in muscle mass, fat and body water.
In elderly individuals with respiratory allergies, the ‘course’ of the disease is
considered too advanced, and therefore the therapeutic value of specific immunotherapy
is considered very limited. Physicians often face the requests of patients who ask
for complementary/alternative medicines (CAMs). Thus, it is urgent to become aware
of the efficacy and contraindication of CAMs in order to provide patients with scientifically-supported
information, especially in older populations. Strategies to increase physical and
sports activity participation among older people should include the awareness of the
benefits and minimize the perceived risks of physical activity. Despite advances in
the management of asthma independently of age, there is an urgent need for targeted,
disease-modifying asthma treatments. It is necessary to clearly identify clinical
phenotypes to achieve optimal treatment of elderly patients with asthma. It is clear
that the delivery of biologics or advanced immunotherapy requires a special attention
in the elderly, where comorbidities are often present.

The current article undergoes the main aspects of pharmacological and non pharmacological
approaches to asthmatic subjects of advanced ages, with special focus on safety issues,
and highlights the practical considerations to be taken into account when managing
elderly asthmatics in clinical settings.

Inhaled treatment

Corticosteroids

Inhaled corticosteroids (ICS) are widely used in the treatment of patients with asthma,
in that, they represent the cornerstone of the pharmacological management of the disease.
However, high-dose regimens and long-term use of ICS may be associated with increased
risk of side-effects, which are mostly important in the elderly populations. The GINA
guidelines 1] clearly state that asthma treatment in the elderly is complicated by several factors,
such as the reduced coordination between activation of the device and inhalation of
the drug, which can affect the lung deposition on one hand (thus reducing the efficacy),
and can increase the oral deposition on the other hand (thus causing local and systemic
adverse events). In addition, the increased number of comorbidities and their associated
symptoms and treatment may interact to various extent with the pharmacological treatment
for asthma, potentially leading to serious side effects.

The pharmacokinetic and pharmacodynamics features of the ICSs are influenced by several
factors, such as the particle size and the formulation of the aerosol. These factors
can affect the systemic bioavalaibility, which is responsible for the potential suppression
of the hypothalamic-pituitary-adrenal axis. The bioavailability is also influenced
by the protein binding and the process of bioactivation by first pass metabolism of
the liver. All these passages can be altered in the most advanced ages, and should
be taken into account, by using the minimum efficacy dose of ICS.

With no doubt, the most serious potential side effect is the increased incidence of
pneumonia, which has been observed in patients with COPD both in controlled clinical
trials and case–control analyses 2]. There is evidence that the occurrence of pneumonia is associated with the use of
ICS also in asthma 3]. Because of the long-term use of ICSs, safety concerns have been raised with regard
to osteoporosis and risk of fractures 4], although the occurrence is much lower in comparison with the use of systemic corticosteroids.
The clinical implications for elderly asthmatics may not be trivial, since these subjects
will likely continue to be exposed to high doses of ICS over many years.

Patients and physicians are often concerned about the use of ICSs and the occurrence,
or worsening, of diabetes. Suissa and collaborators 5] found that ICS use was associated with a 34% increase in the risk of incident diabetes,
defined as initiation of anti-diabetic medications, in a dose–response fashion. Moreover,
in patients already treated for diabetes with oral hypoglycemic agents, the risk of
progression to insulin also increased significantly with the use of ICS. With regard
to the occurrence of glaucoma and cataract, the available literature has not confirmed
the link with the chronic use of ICS 6],7], although a careful check for ocular abnormalities and the monitoring of ocular pressure
is always recommended. Local side effects, such as oral, pharyngeal and even esophageal
candidiasis are common adverse effects of ICS. However, little is known about the
prevalence in the elderly. It is logical to assume that factors such as the patient’s
inhalation technique, patterns of inhalation and peak inspiratory flow, all of which
are variably impaired in elderly patients, can increase the occurrence of these side
effects in the most advanced ages 8],9].

Beta-2 adrenergic agonists

Beta-2 agonists, both short- and long-acting (SABA and LABA), are widely used in elderly
asthmatic patients and their efficacy is well established 8],10]. Aside the valid and prolonged bronchodilator effect, long-acting molecules may also
exert a beneficial steroid sparing action if added to moderate dose inhaled corticosteroids
instead of increasing the use of the latter. The chronic use of beta-2 agonists can
however lead to the onset of tolerance. This has been mainly reported in specific
phenotypes of asthma like exercise-induce bronchoconstriction (which shares a prevalent
neutrophilic inflammatory pattern with elderly asthma) and in peculiar subpopulations
of subjects, despite data in aged patients are not available in literature. Furthermore,
responsiveness to this class of drugs may decline with age, due to a beta-adrenergic
dysfunction 10]. In addition, clinicians should limit the prescription of SABA to that for rescue
therapy, advising any patient using them more than twice weekly to return for reassessment
of asthma control.

Besides these general indications, there are certain therapeutic concerns related
to the beta-2 adrenergic administration, unique to older patients, which deserve to
be addressed. Among these, the most important seems to be the greater probability
of adverse effects, in the setting of multiple comorbidities 11]. Hypokalemia, QT prolongation, tachycardia and tremor are the side effects more commonly
reported in association with these agents. They are mediated by the systemic drug
absorption and are dose dependant. In particular, the incidence of dysrhythmias after
the administration of nebulized beta-2-agonists is well recognized and it has been
reported to be as high as 65% 12]. However, clinical trials have not specifically addressed the use of SABA and LABA
in elderly asthmatic patients. This is unfortunate, since the incidence of ischemic
heart disease and the coexistence of other cardiovascular disorders increase with
age, and many patients with chronic lung disease are smokers. Furthermore, beta-2
agonists cause a net influx of intravascular potassium into cells with subsequent
hypokalemia. Older patients taking diuretics or insulin, as well as those with poor
nutritional intake have a greater incidence of hypokalemia and are thus at greater
risk of developing this common electrolyte disturbance.

Anticholinergics

The use of anticholinergic drugs in elderly should take into consideration the detrimental
effect of aging on the parasympathetic activity and the possible occurrence of adverse
events. Ipratropium bromide is a short-acting anticholinergic bronchodilator that
is routinely used for COPD, and is less commonly used as first-line therapy to treat
asthma. However, ipratropium is often prescribed in combination with albuterol for
the treatment of acute exacerbations of asthma in emergency rooms. Results of previous
research studies showed the benefit of using the combination therapy in adults with
acute asthma (mean age 34.3?±?10.5 years), leading to a decreased rate of hospital
admission compared with albuterol alone 13]. Tiotropium has been considered as add-on therapy to ICS and LABA, and the results
of randomized controlled trials suggest a significant effect on lung function. However,
all trials enrolled adults with an overall mean age of 49?±?11 yrs, preventing, at
present, definitive conclusion about the efficacy of tiotropium in elderly asthmatics
14]-16].

Long acting anticholinergic are well tolerated in the elderly. Dry mouth, and unpleasant
taste can occur and these adverse events can contribute, in older people, to reduced
ability to speak, mucosal damage, denture misfit, poor appetite, malnutrition risk
and respiratory infection due to the reduction of antimicrobial activity of saliva.
In males, urinary outflow can be observed and a reduction of gastrointestinal motility
has been documented in adults. Moreover, anticholinergics increase intraocular pressure
and can cause dilatation of pupil and blurred vision. Cardiovascular effects have
been deeply explored in COPD patients, and the available results regarding their safety
may be considered encouraging. Due to the reduced metabolism and drug elimination
in older patients, anticholinergic drugs may induce, in continuous users, mild cognitive
impairment. Finally, in 3 patients out 1000 a paradoxical bronchocostriction may occur
17]. On the basis, the use of long acting anticholinergic drugs should be limited to
elderly people that remain uncontrolled despite ICS and LABA use, LABA intolerance
and ineffectiveness of other therapeutic approaches.

Systemic treatment

Systemic glucocorticoids

Systemic glycocorticoids (mainly administered by oral route) are listed as second
line option in GINA guidelines step 5 and at low dose (i.e. 7.5 mg/die equivalent
of prednisone). Their use is limited to adults with poor control and reserved to elderly
patients who may have more benefit than side effects, which increase with the dose
administered. They are to be administered when flares-up of symptoms develop in the
course of well-controlled treatment and when acute emergency occurs, including hospital
care. Use of oral steroids in asthma was more liberally prescribed in the past, when
the concepts of steroid-resistance and dependence were developed. Nowadays, systemic
steroids are the final approch when all other strategies have failed or are not applicable.
About 40% of asthmatic patients above 75 yrs of age do not control their asthma, and
this is only partly related to cortisonophobia of both patients and doctors. Obesity
is another factor predisposing to diminished steroid response, even after adjusting
for body weight. When serious life threatening acute episodes occur, or on emergency
hospital admission, prednisolone at 1/mg/kg (with maximum of 50 mg) is recommended
18]. From a clinical perspective, it is interesting to point out that oral route (when
not contraindicated) is as efficacious as the intramuscular or intravenous routes.
Therapy should not exceed seven consecutive days, but no problems arise from abrupt
discontinuation for treatments below 14 days. Beyond this time frame, a gradual titration
of oral steroids is advisable.

Side effects due to systemic glycocorticoid treatment include glucose intolerance
(usually reversible or controlled by treatment), gastrointestinal bleeding (in patients
with known disease or gastrectomized for previous ulcers) and blood pressure control
(not a main problem since step-up antihypertensive therapy controls the increase).
Depression and changes of mood are frequent, especially in the elderly populations,
and other side effects such as catharact, glaucoma, osteoporosis and adrenal insufficiency
may occur in the long-term treatment. The danger of immunosuppression is not common
and it is even less frequent than with inhaled corticosteroids (i.e. candidiasis,
tuberculosis). When elderly patients are discharged from hospital, adherence to treatment
abruptly ceases and a flare-up of symptoms after discontinuation of systemic steroids
is considered a bad prognostic sign and indication of greater severity of asthma 19].

Leukotrienes antagonists

There are two different licensed leukotriene (LT) Antagonists (LTRA) for asthma treatment:
a) a 5- lipoxygenase enzyme inhibitor named zileuton, and three LT-1 antagonists named
montelukast, pranlukast, zafirlukast. In the COMPACT 20] study montelukast showed its ability to spare on ICS dosage doubling ICS to obtain
asthma control; while in the IMPACT 21] study montelukast showed its ability to be an alternative to salmeterol in patients
treated with fluticasone propionate. When considering this option in the elderly,
a recent observational study on asthmatics ?65 yrs reported that about in a quarter
of them montelukast was used as add-on therapy to a LABA/ICS combination 22]. Theoretically, montelukast could be of interest in the treatment of asthma in the
elderly, as it could contribute to obtain symptom control by enhancing patients’adherence,
frequently reduced in the elderly 23], increasing the efficiency of asthma therapy, by counterbalancing well-known errors
in managing inhaler devices, also frequent in the elderly 24], and avoiding ICS and LABA side effects, reported with higher frequency in the elderly
25], and considered a component of the future risk of asthma. It is of interest the ability
of LTRA to be an alternative to ?2 agonists when hypertension and/or hearth failure
and/or chronic ischemic heart disease are present, becoming the first-line drugs for
elderly asthmatics with a history of cardiovascular events. Moreover, avoiding a low
dose ICS or sparing on its doubling dosage may be useful when comorbidities are present
(osteoporosis, diabetes, glaucoma, cataract). In one double blind, randomized, placebo-controlled
study on subjects aged 60 yrs with severe asthma, control was improved by adding
montelukast to LABA/ICS combination. Subjects experienced reduced exacerbations, asthma
symptoms and salbutamol use 26]. The authors hypothesized that these positive effects were due to higher adherence
to the once daily oral treatment with added montelukast. However, a retrospective
analysys on five clinical trials 27] comparing zariflukast and fluticasone propionate did not show any significant benefit
on a population aged 50 yrs. A recent revision of Scichilone et al. 28] on the safety and efficacy of montelukast in the elderly population is reassuring
about safety, but is unable to conclude for a superior efficacy of LTRAs in this setting.
However, the authors concluded that in the elderly population LTRAs, and particularly
montelukast, may represent a more effective strategy in improving asthma given unintentional
nonadehrence with inhalation therapy.

Theophyllines

Theophylline, a methylxanthine, has been used as a bronchodilator in the treatment
of asthma for more than 80 years, and remains a widely prescribed drug, because it
is cheap and readily available 29]. Unfortunately, relatively high doses of theophylline are required to obtain a bronchodilator
effect (10–20 mcg/ml), and this is associated with high incidence of side effects,
mostly due to adenosine antagonism 30]. Theophylline treatment is also limited by its narrow therapeutic range, variable
inter-patient pharmacokinetics, and multiple drug interactions. However, in recent
years, the interest for theophylline is reborn through the demonstration of its anti-inflammatory
activity 29],31]. Actually, even at low therapeutic concentrations (5 mcg/ml) it is able to activate
the histone deacetylases, especially when their activity is reduced by oxidative stress,
as in smokers 32].

In general, the use of theophylline is limited by its adverse effects, which range
from commonly occurring gastrointestinal symptoms to palpitations, arrhythmias, rarely
myocardial infarction and seizures. Theophylline is metabolized primarily by the liver,
and commonly interacts with other medications. The available data indicate that the
clearance of theophylline is reduced by 22-35% in elderly people, and that it is furtherly
decreased by concomitant diseases, particularly liver (50% decrease) and heart (50%
decrease) disease. Theophylline clearance is also influenced by diet: low carbohydrate/high
protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef
increase the clearance and decrease half-life. Curiously, theophylline clearance is
increased by 80% in elderly tobacco smokers. However, appropriate studies have not
demonstrated geriatric-specific problems that would limit the usefulness of theophylline
in the elderly. In conclusion, the main roles of theophylline in asthma of the elderly
are in severe disease as an adjunct to ICS and LABA, particularly in conditions of
corticosteroids resistance and in smokers 33]. Caution and close monitoring of plasma theophylline concentration are required in
the elderly.

The phosphodiesterase (PDE) 4 inhibitor roflumilast is available for COPD treatment,
and its use in asthma can be an interesting add-on therapeutic option in severe asthma
with frequent exacerbation and neutrophilic inflammation. Its therapeutic use of is
limited by side-effects, which are dose-dependent and the range of efficacy/tolerability
is narrow. No difference in safety or efficacy was found between older and young patients
and no cardiovascular risks emerged in studies 34]. The main limitations are associated with class-specific side effects such as emesis,
reported as a dose-limiting side effect, nausea and diarrhea. Weight loss is a major
concern, reported in daily clinical settings.

Monoclonal antibodies

To date, omalizumab, a monoclonal anti-IgE humanized antibody, is the only specific
target therapy available, and recognised as an add-on therapy in severe persistent
asthmatics with inadequately controlled symptoms, regardless of age. Despite the high
safety profile of omalizumab, an association between the use of omalizumab and the
occurrence of hyperglycemia has been recently documented, and related to the sucrose
contained in the vials 35]. Taking into account the incidence of diabetes in elderly patients, clinicians must
control the blood levels of glucose in asthmatic patients during omalizumab treatment.

Infliximab, a chimeric anti-TNF-? monoclonal antibody (mAb) and etanercept, a soluble
TNF-? receptor linked to human Fc of IgG1, showed significant improvements in lung
function and in the exacerbation rate, particularly in patients with severe steroid-resistant
asthma. However, conflicting efficacy results obtained with other TNF-? blockers have
cooled the use of these biologicals in asthmatic patients 36]. The crucial role of IL-5 in eosinophil activation, maturation and survival makes
it an interesting drug target. In fact, the inhibition of eosinophil accumulation
in the airway wall of asthmatic patients by using mepolizumab and reslizumab, two
humanized anti-IL-5 mAbs, and benralizumab, an anti-IL-5 receptor represent novel
therapeutic strategies. IL-4 is an established clinical target and a key factor in
airway inflammation and IgE synthesis by B cells; however, despite initially promising
findings with biologics able to block its functions (pitrakinra, pascolizumab, dupilumab),
subsequent trials are needed before its clinical application 37]. In conclusion, other than the anti-IgE mAb omalizumab, novel therapies are currently
being explored to overcome the difficulties of severe asthma, even though no specific
treatment are dedicated to older asthmatic patients.

Specific immunotherapy

Subcutaneous immunotherapy

Subcutaneous immunotherapy (SCIT) is the historical route of administration and consists
of allergen extract injections which can only be performed with a medical observation.
The guidelines on the treatment of allergic diseases rarely focus on the elderly population
and often ignore this population completely. Several placebo-controlled studies that
demonstrated efficacy have included subjects up to 60 years of age. Unfortunately,
studies that support the safety and effectiveness of SCIT in the elderly are not blinded.
The European Academy of Allergy and Clinical Immunology advises specific immunotherapy
as a relative contraindication for elderly patients 38]. The Canadian Society of Allergy and Clinical Immunology, in its guidelines for the
use of immunotherapy, does not contraindicate this treatment for aged patients 39]. However, the presence of co-morbid cardiac or pulmonary conditions might increase
the risk of a poor outcome following a systemic reaction. Other factors/co-morbidities
to consider before starting immunotherapy in the elderly are: severe or unstable asthma,
beta-adrenergic blocker and angiotensin converting enzyme inhibitors (ACEI) therapy,
autoimmune diseases, and neoplastic diseases. There are potential elements of risk
that can be influenced by beta-adrenergic blockers in the setting of vaccine administration.
Reactions might be more frequent, more severe, and refractory to treatment 40]. Concomitant treatment with beta-adrenergic blockers does not appear to increase
the risk for sistemic reaction to SCIT, but may result in more protracted and difficult
to treat anaphylaxis. There is an ongoing debate on whether ACEI should be substituted
prior to initiation of immunotherapy for safety reasons 41]. The medical literature reports no double blind placebo controlled (DBPC) studies
specifically evaluating the efficacy of SCIT in elderly asthmatic patients. However,
the prevalence of IgE-dependent allergic rhinitis and other atopic diseases in elderly
patients is reportedly increasing. Based on the lack of the studies conducted to date,
there is a clear need to design DBPC studies on a large scale with a significant number
of patients enrolled to evaluate the efficacy and safety of the immunotherapy in the
elderly; then it will be essential to confirm the results obtained in these large
studies in the real-life setting 42].

In conclusion, we are in agreement with the statements reported in the “Third Update
Practice Parameter on Allergen Immunotherapy” which recommend that the risk/benefit
assessment for SCIT should be carefully evaluated in the elderly population because
they might have co-morbid medical conditions that could increase the risks 43]. However, there is no absolute upper age limit for initiation of SCIT. Contraindications
to immunotherapy in elderly patients are medical condition that reduce the patient’s
ability to survive a systemic allergic reaction (i.e., patients with markedly compromised
lung function), poorly controlled asthma, unstable angina, recent myocardial infarction,
significant arrhythmia, and uncontrolled systemic hypertension.

Sublingual immunotherapy

The awareness of the efficacy and safety of allergic specific sublingual immunotherapy
(SLIT) in geriatric patients is sometimes controversial. In part it is also due to
the disbelief of the clinical benefits, and of the positive impact on health care
costs in this age of life. In addition, it is generally known that the immune system
in the elderly is down-regulated in comparison with young people and that allergies
do not occur, so as not to require any more therapy. However, the reports of increased
levels of total and specific IgE and consequent increase in immunological disorders
are raising in literature in the last few years 44]. From the economic point of view, the impact of this treatment on the direct and
indirect costs should also be outlined. Two prospective assessments of treatment in
sublingual tablets for grasses, conducted in the Northern and Southern Europe, have
shown that SLIT is a treatment with a favorable cost/effectiveness ratio 45],46].

Recently, it has been proved that the dendritic cells (DCs) in the elderly have an
activated phenotype and an increased secretion of pro-inflammatory cytokines, which
are responsible for the infiltration of eosinophils, the airway remodeling and the
increase of asthma and chronic respiratory diseases 47]. In the SLIT the oral DCs are the first structures involved in the mechanism, with
the aim to modulate the allergen-specific antibody responses. With particular reference
to the geriatric age, compared to subcutaneous therapies it has the advantage of a
home management that greatly simplifies the life of old people, who generally have
difficulties in moving. In a retrospective study, Marogna et al. 48] evaluated the effect of SLIT in older patients sensitized to house-dust mite in the
prevention of rhinitis and asthma progression, but also in reducing the symptoms and
consumption of drugs. This was recently confirmed in a double-blind placebo-controlled
study in patients over 60 years of age 49].

The safety of SLIT is confirmed by the fact that after more than 500 million doses
administered to humans and 20 years of use there are no reports of fatalities; only
few cases of anaphylaxis have been reported 50]. According to the Bozek et al. 49], only three patients among the elderly had local common side effects such as oral
itching and facial flushing. No severe adverse reactions were observed in the active
group during the study, thus confirming that SLIT is well tolerated in elderly patients.
However, the compliance to SLIT may represent a major problem in real life, especially
in the elderly populations.

SLIT has been demonstrated to reduce significantly both symptoms and medications,
thus improving quality of life (QoL) 51]; this could be of great importance with regard to the elderly population. In fact,
recent studies point out that the quality of life is significantly reduced in old
people with allergic rhinitis in comparison with young people, and it can also alter
the cognitive function or the mood 52].

In conclusions, SLIT is an effective and safe therapeutic option, and the only approach
that can change the course of allergic respiratorydiseases; however, its use in the
elderly is still not widespread. A prerequisite before starting on a SLIT, especially
in the geriatric patient, is to involve the allergic patient through correct information
about the various aspects of his disease: from diagnosis, pharmacological treatment
options, costs, side effects, management methods, thus to verify if the patient is
able to deal with the SLIT.

Probiotics

The United Nations Food and Agricultural Organization and the World Health Organization
define probiotics as “live microorganisms, which, when administered in adequate amounts,
confer a health benefit to the host” 53]. Prebiotics are defined as non-digestible oligosaccharides, such as fructo-oligosaccharides
and trans-beta-galacto-oligosaccharides, that selectively stimulate the growth of
bifidobacteria and lactobacilli, thus producing a prebiotic effect. Synbiotics is
a term referring to the use of both prebiotics and probiotics simultaneously. In taxonomy
terms, the most commonly used probiotic bacteria are species of the genera Lactobacillus
and Bifidobacterium. There are several mechanisms by which probiotics are proposed
to exhibit beneficial effects on the host: most probably probiotics can modulate the
toll-like receptors to promote TH1-cell differentiation, inhibition of antigen-induced
T-cell activation and suppression of TNF 54]: the resulting stimulation of Th1 cytokines can suppress Th2 responses. A variety
of human studies on the effects of probiotics administration on the management of
various allergic diseases have been performed to examine the efficacy of probiotics
in many allergic conditions, such as eczema and food allergy but there are limited
studies on the effect of probiotic treatment for asthma that do not allow the reader
to extract concrete conclusions that would be useful for everyday practice 55]. In addition, there is no study specifically addressing the use of probiotics in
elderly asthmatics, and therefore no indication can be posed for this phenotype.

Vaccinations

In older people, alterations of both innate and acquired immunity have been shown
(Table 1), resulting in an increased susceptibility to infectious diseases. Viruses, including
influenza, cause acute exacerbations of asthma in as many as half of adult subjects
presenting to emergency rooms. Vaccines play a major role, potentially preventing
or worsening of asthma symptoms. Therefore, vaccines, such as against influenza and
pneumococcus, should be administered to these patients. Asthma was the most common
underlying condition among old individuals hospitalized with pandemic influenza A
(H1N1) infection 56]. All asthmatics should receive an influenza vaccination annually 57]. This is in accordance with the statement of the Task Force on Community Preventive
Services, which recommends multicomponent interventions aimed at increasing influenza
vaccination coverage 58]. In addition, asthma education for health-care professionals should include recommendations
for influenza vaccination for all patients with current asthma. Although it was hypothesized
that influenza vaccination may cause wheezing and adverse effect on pulmonary function,
there is no significant increase in asthma exacerbations immediately after vaccination
in adults or children over 3 years of age.

Table 1. Immunological changes occurring in older individuals compared to younger ages

Respiratory bacterial infections are among the most important causes of morbidity
and mortality from communicable diseases worldwide. Streptococcus pneumoniae frequently
colonizes the upper respiratory tract. Local host immunity is essential to control
colonizing pathogens by preventing overgrowth, spread, and invasion. Asthma is commonly
considered an independent risk factor for invasive pneumococcal disease. The pneumococcal
conjugate vaccine, PCV13, is currently recommended for all adults 65 years or older,
in particular in older asthmatics. The 23-valent pneumococcal polysaccharide vaccine
PPSV23 is also recommended for use in adults of 65 years of age who smoke cigarettes
or who have asthma. Physicians and other health care professionals should therefore
encourage vaccinations in elderly asthmatic patients.

Alternative medicines

The use of Complementary/Alternative Medicines (CAMs) is an impressive emergent phenomenon
in Western Countries. This widespread use is common at any age, including older people
59]. Bronchial asthma is an important field for CAM, where homeopathy, acupuncture, herbal
medicines and yoga are the most utilized techniques 60]. The reasons for using CAMs usually reported by patients are: a distrust in conventional
medicine, the belief that CAMs are more natural and safe, and the need for a more
strict relationship with the physician 60]. Due to the large diffusion of CAM, the high prevalence of allergic diseases, and
the not negligible costs, it is definitely needed that proofs of efficacy are incontrovertible
61]. Only randomized controlled trials can be suitable for the evaluation of CAM efficacy
and safety. However, the vast majority of the clinical trials published up today with
CAMs have a low qualitative level 62], thus making the results often difficult to interpret. On the other hand, it is claimed
that “holistic” approaches cannot be standardized and submitted to rigorous study
designs, because the standardization itself introduces a confounding factor 63]. Finally, it has to be considered that some of the CAM techniques are self-applied
(Yoga, relaxation techniques, biofeedback) and therefore cannot be blinded.

Acupuncture

Acupuncture is a cornerstone of the Traditional Chinese Medicine, and is widely used
for chronic illness, including asthma. The most recent reviews 64] included 11 studies with 324 participants: trial reporting was poor, and quality
was judged insufficient. Indeed, looking only at those studies performed with a rigorous
methodology (i.e. randomized, controlled and blinded), the effects of acupuncture
are not different from the placebo treatments. Thus, the conclusion derived from meta-analysis
studied and clinical trials is that acupuncture is not effective to treat asthma,
although a powerful placebo effect of acupuncture as rescue medication was demonstrated
65].

Homeopathy

Homeopathy is based on the belief that symptoms of a disease can be cured by the same
substance that provokes them, if given at ultra-dilution. Homeopathic remedies are
therefore chosen according to symptoms, not to disease, and prepared with a special
manual technique called “potentiation”. Homeopathy has been extensively studied in
allergic diseases, and there are well-conducted and rigorous trials in both asthma
and rhinitis, 66]-68], but none on elderly: these studies failed to demonstrate a mesurable clinical benefit
on symptoms and functional parameters in adults 66],67].

Phytotherapy

The traditional allopathic medicine is largely based on subtances derived from plants
and herbs (e.g. theophillyne, salycilates, digitalis, morphine). The literature on
herbal remedies is impressive, due to the large variety of herbs and their combinations
used: tylophora indica, boswellia serrata, pychrorryza kurroa, koleus forskholii, gynko
biloba, urtica and others. All these studies are in general of low quality, but in many cases, a
clinical effect can be measured in several diseases, including bronchial asthma. This
is not surprising, because most of the herbs utilized contain pharmacologically active
ingredients. Positive results were obtained in rhinitis and asthma with the mixtures
of herbs used in the traditional Chinese medicine, which contain ephedrine and atropine.
No study has specifically addressed its use in older populations. The active ingredients
may also induce undesirable side effects 69]. Moreover, at variance with proprietary marketing drugs, herbal remedies carry the
risk of adulteration, incorrect collection of plants, wrong preparation and inappropriate/incorrect
dosing 70]. Products containing ginseng may negatively affect the anticoagulant and hypoglycemic
therapies 71], which may have dramtic consequences in older individuals. Of note, herbal remedies
can be responsible for severe allergic reaction more frequently in atopic subjects
72].

Behavioral, physical and other complementary treatments

Physical techniques (e.g. breathing control, Yoga techniques and chiropractic/spinal
manipulation) have been proposed in patients with chronic respiratory illness with
the aim of improving the respiratory pattern. The majority of clinical trials of chiropractic/spinal
manipulation in asthma 73],74] failed to demonstrate a clinically relevant effect. Although breathing and yoga techniques
can have some effect on self-perceived well being, they cannot be recommended as an
effective treatment for asthma 75]. Also behavioral techniques such as biofeedback and hypnosis have been sometimes
applied in asthma, generally in low quality studies, but the overview of the literature
concluded for no effect 76],77].

In conclusions, available scientific evidence does not support a role for CAM in the
treatment of asthma in the elderly. The studies in the literature often have significant
design flaws that weaken the conclusions such as insufficient number of patients,
lack of proper controls and indadequate blinding.

Exercise and sport

For the elderly asthmatic, exercise represents at the same time both a goal and a
precious tool for treatment. On the one side, in fact, regular participation in sports
and physical activity is one of the best ways for older adults, including those with
chronic diseases, to promote independence, increase quality of life and improve aerobic
capacity, breathing pattern, muscle strength 78]. On the other side, older asthmatics may develop a negative attitude to exercise
due to a fear of symptoms occurring during or after exercise and to a lack of specific
advice about exercise from specialized health professionals 79]. This lowers significantly the level of habitual activity and physical fitness, and
the result is that older asthmatic are less active than their non-asthmatic peers
80]. To date, the majority of studies evaluating exercise training in asthma have been
performed in children or young adults with mild-to-moderate persistent disease. Practicing
any kind of sports in the elderly asthmatic must firstly consider the physiological
changes in old age: loss of muscle mass; reduction in bone mass; increased percentage
of fat; lower amount of body water; lack of thirst; diminishing kidney function and
the very frequent presence of comorbidities, in particular related to the cardiovascular
system. The regressive changes in the locomotor and the nervous system of the elderly
may reduce strength, endurance, proprioceptive capacity (e.g. coordination, balance)
and mobility 81]. While numerous studies deal with general physiology and sports medicine aspects
in the elderly, very scant specific literature is available about asthmatic senior
subjects and sports.

Exercise-induced bronchoconstriction (EIB) with- and without underlying asthma may
occur also in the elderly asthmatic practicing sports, even with a higher frequency
than in the general adult population taking into consideration all the comorbidities
and physiological changes associated with aging previously cited. Sports with prolonged
effort of more than 5–8 minutes or in cold and dry environments represent major risk
factors (e.g. endurance sports, cycling, cross-country skiing). Swimming is still
a controversial issue, and therefore it should be avoided for the potential risk related
to chlorine byproducts inhalation. Treatment should follow the general guidelines
and recommendations that apply to adults, with the limit of an arbitrary extrapolation
due to the paucity of specific clinical trials in patients over 65 years. Finally,
elderly athletes involved in International Association of Athletics Federations (IAAF)
or in official masters’ competitions, must be aware about anti-doping regulations
that apply not only to some anti-asthmatic drugs (beta-2 agonists except salbutamol,
salmeterol and formoterol; systemic corticosteroids) but also to several drugs widely
used to treat older adults’ comorbidities (e.g. beta-blockers, diuretics, hormones).

Age-related and concomitant disease issues in asthma treatment

Adherence

The contribution of patient adherence to clinical success cannot be overestimated
82], and clinicians should always be aware of the role played by patients themselves
in determining the success or failure of treatment. These general concepts apply perfectly
to asthma, whose management is mainly based on the use of inhalation therapy. In the
elderly, unintentional non adherence with inhalation therapy may lead to significant
impairment in asthma control. Elderly patients often are affected by several chronic
diseases requiring multiple medications. Complexity of the treatment can be considered
a major risk factor for reduced adherence with medication. In addition, elderly patients
may suffer from cognitive, hearing, or visual impairments, or other physical inabilities
(such as arthritis, tremor, and low coordination) that significantly affect their
ability to understand and follow treatment regimens. Despite the evidence that asthma
related morbidity and mortality are higher in the elderly than in the young asthmatics,
the research studies and health policies on asthma have focused mainly on children
and young adults. The recently published National Institute on Aging (NIA) white paper
highlighting the burden of elderly asthmatics emphasizes the need for further research
to identify and intervene on factors affecting the disease in this under-studied group
of patients 83]. Beliefs about treatment, such as the notion that treatment is not necessary or safe,
are also correlated with decreased adherence and lower prescription refill. The beliefs
are frequently held by elderly asthmatics, yet their influence on medication adherence
has not been demonstrated among these patients 83],84]. In conclusion, an improvement of adherence is likely required to prevent the lack
of treatment in chronic diseases, and in particular in the elderly asthmatics.

Comorbidities

Aging is associated with the development of numerous chronic diseases. Thus, it is
quite common that elderly asthmatic subjects have additional chronic diseases, which
may interfere with adherence to asthma treatment and control. Many epidemiological
studies 85],86] report that, within the elderly population??65 years, asthmatic patients would have
an increased incidence of additional chronic diseases than the rest of population.
Arthritis, insomnia, gastric ulcers, migraine, sinusitis, depression, cancer, and
atherosclerosis were significantly more prevalent in patients with chronic airway
obstruction (both asthma and COPD) according to a Dutch study 86]. In the US, Diette et al. reported that comorbid conditions, specifically COPD, heartburn,
and congestive heart failure, were more prevalent in patients over 65 years of age
than younger patients 87]. Depression has been reported to be associated to severe asthma in the elderly from
U.S. National Heart, Lung, and Blood Institute’s Severe Asthma Research Program 88] and, in a cohort of elderly inner-city asthmatic patients, depressive symptoms were
associated with poorer asthma control and quality of life, as well as with lower rates
of adherence to controller medications 89].

The impact of comorbidities on asthma control of elderly asthmatics has been explored
by few studies with conflicting results. According to a Canadian study 90], although more than 83% of patients with asthma who were 55 years and older reported
having one or more major comorbidities, the odds of having asthma symptoms or attacks
for these patients were lower than the odds in younger. On the other hand, in the
same study, the odds of self-perceived health status as fair or poor were significantly
higher in the older respondents with asthma (70 years and older: OR 3.10, 95% CI 2.27
– 4.12) and those with five or more comorbidities (OR 35.18, 95% CI 19.57 – 63.26).
The recent findings from the Italian multicenter study on elderly asthmatics (ELSA
study) showed that elderly patients with asthma associated with COPD had worse asthma
control and higher rate of severe asthma exacerbation in the previous year, compared
to asthmatic patients without COPD 22]. In conclusion, elderly asthmatic patients have many comorbidities, which, with the
possible exclusion of COPD and depression, do not seem to have a direct impact on
asthma control in patients under specialist care. Nevertheless, the comorbid conditions
in the elderly patient makes the diagnosis of asthma more difficult, so that elderly
asthmatic patients appears to be undertreated, with the consequence of a higher hospitalization
rate and mortality.

Asthma and concomitant rhinitis

Asthma is frequently associated with nasal/sinonasal comorbidities such as rhinitis
(allergic and non-allergic) or chronic rhinosinusitis (with and without nasal polyps),
and these conditions may act as aggravating factors for asthma itself. Rhinitis in
the elderly seems to have peculiar clinical and cytologic characteristics 52], and the strong association with asthma seems to be confirmed 91],92]. Therefore, treating concomitant rhinitis or chronic rhinosinusitis is part of the
correct and global management of asthma also in older adults.

Antihistamines

Antihistamines are a mainstay in the treatment of allergic respiratory diseases due
to their H1 receptors antagonism. The first-generation anti H-1 (e.g. chlorpheniramine,
diphenhydramine) are effective on allergic inflammation but they have well-known side
effects, due to the lack of specificity for the H1 receptor 93]. Sedation, anxiety, confusion and decreased reaction time are more pronounced in
the elderly, as well as the anticholinergic effects, such as drying of the mouth and
eyes, blurred vision, disequilibrium, urinary retention and constipation, arrhythmias
and postural hypertension. For these reasons symptomatic prostatic hypertrophy, bladder
neck obstruction and narrow angle glaucoma should be taken into consideration as contraindications
to the use of first-generation antihistamines 93],94]. The potential cardiac toxicity deserves some considerations. It is not a class effect
and does not occur through the H1-receptor. Nevertheless it has been described that
some first-generation H1-antihistamines, such as promethazine, brompheniramine, diphenhydramine
in some cases are able to prolong the QT interval, and potentially cause serious polymorphic
ventricular arrhythmias such as torsades de pointes. These effects have been observed in case of large doses of overdoses, however the
potential cardiac comorbidities should be carefully assessed when prescribing an antihistamine
drug 93]. The changes in body composition and the decreased activity of liver in the elderly
may account for a major risk of adverse events associated with first generation H1-antihistamines
use 94],95].

The second-generation of H-1 receptor antagonists (e.g. loratadine, cetirizine, fexofenadina,
desloratadina, levocetirizina) provide a better safety and tolerability profile due
to their low cross blood brain barrier and greater specificity for their receptor
96]. The propensity of two second generation H1-antihistamines introduced in the 1980s,
astemizole and terfenadine, to exert a cardiac toxic effect has been described 93]. These two drugs are no longer approved by regulatory agencies in most countries.
No or not clinically significant cardiac effects have been reported for the second-generation
H1-antihistamines loratadine, fexofenadine, mizolastine, ebastine, azelastine, cetirizine,
desloratadine, levocetirizine, rupatadine and bilastine 96]. Second generation antihistamines have little or no sedative or anticholinergic effect
96]. However, because of the reduced metabolic activity, treatment should be started
with a lower dose in this age group. In fact some second-generation H1-antihistamines
such as desloratadine, loratadine and rupatadine are metabolized by the system cytochrome
P450. Cetirizine is excreted largely unchanged in the urine, and fexofenadine is excreted
largely unchanged in the feces. However interactions may be more likely to be associated
with first generation H1-antihistamines than second-generation H1-antihistamines,
which have a wider therapeutic index 96]. Thus it is recommended to use second-generation antihistamines in the elderly.

Nasal corticosteroids

For many other classes of drugs, clinical trials with intranasal steroids were generally
conducted in adults, typically included those 65 years and older, but without reporting
data specific to this population. However, there is a consensus in considering intranasal
steroids as the first-line treatment for moderate to severe allergic rhinitis in the
elderly, effectively treating all symptoms of rhinitis 97]. A randomized controlled trial studied the effects of mometasone furoate nasal spray
in patients older than 65 years of age suffering from perennial allergic rhinitis,
showing it to be an effective treatment in this cohort 98]. An open-label trial in 18 patients 65 years and older with a history of moderate-to-severe
rhinitis treated with either azelastine nasal spray 2 sprays per nostril bid (1.1 mg)
or fluticasone propionate 2 sprays per nostril qd (200 mcg) for a 6-week study period
showed that both treatments improved symptom scores compared to baseline, with statistically
significant improvement reached earlier for fluticasone compared to azelastine, suggesting
that fluticasone propionate is safe and more effective than azelastine in older adults
99]. Intranasal steroids are generally well tolerated by older patients 100]: the most common encountered side effects are mild epistaxis, dryness, burning and
nasl crusting. In older adults, particular attention should be put for possible systemic
side effects of intranasal steroids, such as effects on bone metabolism which may
rise specific concern particularly in older and postmenopausal women, and in patients
receiving steroids for other concurrent conditions such as asthma itself. However,
based on the lack of significant changes in biochemical markers of bone turnover in
several studies, these intranasal corticosteroids agents do not appear to be associated
with reductions in bone mineral density or osteoporosis 101],102].

Another concern in using intranasal corticosteroids in older patients is the possible
effect of these agents in fostering glaucoma. A case–control study of 9793 patients,
age 66 or older, with a new diagnosis of borderline glaucoma, open angle glaucoma,
or ocular hypertension, and 38325 controls randomly selected showed that there was
no increased risk for these diseases with intranasal steroid use. The risk of ocular
side effects appears to be negligible due to the low systemic bioavailability of most
available intranasal steroid preparations 103]. In conclusion, intranasal corticosteroids have the most favorable safety and efficacy
profiles in older individuals and therefore they should be recommended as first-line
treatment of rhinitis or chronic rhinosinusitis in older patients 104].

Topical antihistamines

Topically administered antihistamines are clinically effective, with the advantage
of delivering the medication directly to the target area. Common adverse events of
inhaled antihistamines are usually mild and include bitter taste, headache, dry mouth,
sedation and application site irritation. More relevant side effects, mainly related
to the first generation molecules, including urinary retention, prolonged QT interval,
arrhythmias and constipation are however more prevalent in elderly patients due to
the commonly observed comorbidities, such as heart diseases, prostatic hypertrophy
and narrow angle glaucoma. Moreover, elderly patients usually take many drugs, thus
increasing the risk of interaction between medications. Therefore, the antihistamine
selection for the treatment of concomitant allergic rhinitis in elderly asthmatic
patients should be made carefully and topical II generation molecules should be preferred
94]. In subjects older than 65 years, azelastine has been shown to be well tolerated
105]. Furthermore, pharmacokinetic studies indicate that the systemic bioavailabilities
of marketed azelastine hydrochloride nasal spray products is about 40% and that 75%
of the excretion of its metabolites is through faeces while just 25% is through urines,
making it safer also for patients with renal impairment 106]. Levocabastine is mainly (about 70% of the absorbed dose) excreted unchanged in the
urine, and has to be therefore used with caution in patients with renal impairment.
After intranasal administration, low plasma concentrations of levocabastine are reached;
therefore, drug interactions are not clinically significant, excluding those with
inhibitor of cytochrome P450, such as erythromycin and ketoconazole. No clinically
significant mean changes from baseline in QT or QT
_c
intervals were reported in literature 107].

At last, a novel intranasal formulation, combining the second generation antihistamine
azelastine hydrochloride and fluticasone propionate in a single device, has been recently
developed, showing superiority over its single components 108]. Although these studies have been performed in a general adult population, we can
reasonably assume the combination could be effectively and safely used also in elderly
patients. Furthermore, the administration of different drugs in the same preparation
could facilitate the compliance for older patients.