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Chronic Obstructive Pulmonary Disease in the elderly

Published:November 01, 2013DOI:https://doi.org/10.1016/j.ejim.2013.10.001

      Highlights

      • COPD is highly prevalent, but it frequently remains unrecognized in the elderly.
      • A relevant proportion of elderly people cannot perform a satisfactory spirometry.
      • COPD dramatically impacts health status of elderly patients.
      • Comorbidity has a major prognostic role but frequently remains unrecognized.
      • Recommendations coming from clinical trials only partly apply to the elderly.
      • The internists should aim at providing a truly comprehensive and effective treatment.

      Abstract

      The prevalence of Chronic Obstructive Pulmonary Disease (COPD) dramatically increases with age, and COPD complicated by chronic respiratory failure may be considered a geriatric condition. Unfortunately, most cases remain undiagnosed because of atypical clinical presentation and difficulty with current respiratory function diagnostic standards. Accordingly, the disease is under-recognized and undertreated. This is expected to impact noticeably the health status of unrecognized COPD patients because a timely therapy could mitigate the distinctive and important effects of COPD on the health status. Comorbidity also plays a pivotal role in conditioning both the health status and the therapy of COPD besides having major prognostic implication.
      Several problems affect the overall quality of the therapy for the elderly with COPD, and current guidelines as well as results from pharmacological trials only to some extent apply to this patient. Finally, physicians of different specialties care for the elderly COPD patient: physician's specialty largely determines the kind of approach.
      In conclusion, COPD, in itself a complex disease, becomes difficult to identify and to manage in the elderly. Interdisciplinary efforts are desirable to provide the practicing physician with a multidisciplinary guide to the identification and treatment of COPD.

      Keywords

      1. Clinical vignette

      An 81-year-old male with a clinical presumptive diagnosis of Chronic Obstructive Pulmonary Disease (COPD) and several comorbidities (hypertension, chronic stable angina, peripheral artery disease, chronic renal failure, severe osteoporosis and diabetes mellitus (DM), Parkinson's disease) presented to the Emergency Department (ED) with progressively worsening confusion and hypersomnolence. Despite the high risk of COPD, due to the presence of chronic productive cough, wheezing and exertional dyspnea, as well as the smoking history (22 packs/year), he had never been definitively diagnosed as affected by COPD because he could not perform an acceptable flow-volume curve maneuver. At admission, he complained of mild chest pain and orthopnea in the last three days. Prior to this acute event, the patient was partially autonomous in basic and instrumental activities of daily living, was able to walk without aids and showed no overt cognitive impairment (Mini-Mental State Examination, MMSE score obtained 6 months earlier: 24/30). However, according to his caregivers, he was poorly compliant to inhalers due to coordination limitation related to his extra-pyramid rigidity. In the past 4 months, he had been hospitalized twice for worsening dyspnea and/or expectoration, and he had experienced a weight loss of about 6 kg. He received annual flu-vaccine and Streptococcus pneumoniae vaccination. His therapy included: inhaled triple therapy (long acting B2-agonists, anticholinergics and corticosteroids), cardio-selective B-blockers, ACE-inhibitors, acetyl-salicylic acid, metformin, glibenclamide, diphosphonates and D-vitamin integration. Vital signs on arrival to the ED were: blood pressure 110/65 mm Hg, heart rate 120 bpm and respiratory rate 28 bpm, oxygen saturation 87% on room air and temperature 36.8 °C. The patient was dehydrated and delirious. Chest auscultation disclosed diminished lung rumors and diffuse mild wheezing. Chest X-ray (CXR) on admission showed diffuse hyper-inflated and hyper-lucent lungs with loss of vascular markings and flat hemidiaphragms; no areas of consolidation were evident. Laboratory analyses demonstrated normal white blood cell (WBC) count, blood glucose of 250 mg/dL, serum lactate of 11 mmol/L, serum creatinine 1.4 mg/dL and urea nitrogen (BUN) 68 mg/dL. Arterial blood gas showed an acute over chronic hypoxemic–hypercapnic respiratory failure with respiratory acidosis (pH 7.33, PaCO2 46 mm Hg, PaO2 41 mm Hg, HCO3 29 mmol/L on room air). The patient was subsequently admitted to the acute respiratory care ward and was started on non-invasive ventilation and ceftriaxone. Hypoxemia, hypercarbia, and the acid–base balance quickly recovered to normal values and delirium disappeared. Supportive therapy consisted of supplemental oxygen, intravenous fluid replacement, diabetes control optimization, prophylactic unfractionated heparin and a personalized diet. Respiratory, hemodynamic, and renal indexes were closely monitored. After 48 h the patient was mentally integer, left the NIV and started the respiratory rehabilitation. The pulmonary function tests after a quick pharmacologic washout were successfully performed by a trained technician and revealed a severe fixed obstruction (FEV1/FVC ratio of 43% and FEV1 34% of predicted value after inhaled bronchodilator trial) associated with an increased air trapping (RV 138% of predicted). A geriatric multidimensional assessment was performed and a comprehensive home care program delivered. After discharge he was regularly assessed at home with regard to long term oxygen prescription and re-trained on how to correctly use inhalers and recognize early symptoms and signs of acute exacerbation. In the following six months the patient regained weight, had less dyspnea and improved physical limitation. He did not suffer any new acute exacerbation of COPD in the following six months.
      This case report includes some of the most common features of COPD in the elderly. These features are the object of this review.

      2. Is Chronic Obstructive Pulmonary Disease (COPD) an age-related chronic condition?

      COPD is a typical disease of aging as its prevalence dramatically increases with age, ranging in the USA population from about 6.6% in the 45–54 year age group to about 12% in >64 age group [
      • CDC
      Chronic obstructive pulmonary disease among adults — United States.
      ]. Data pertaining to European countries refer to the adult or overall, but not to the geriatric population (Table 1) [
      • Geldmacher H.
      • Biller H.
      • Herbst A.
      • Urbanski K.
      • Allison M.
      • Buist A.S.
      • et al.
      The prevalence of chronic obstructive pulmonary disease (COPD) in Germany. Results of the BOLD study.
      ,
      • Stang P.
      • Lydick E.
      • Silberman C.
      • Kempel A.
      • Keating E.T.
      The prevalence of COPD: using smoking rates to estimate disease frequency in the general population.
      ]. COPD accounts for most of the people on long-term oxygen therapy, that is on average a population aged over 70 years [
      • Ekström M.P.
      • Wagner P.
      • Ström K.E.
      Trends in cause-specific mortality in oxygen-dependent chronic obstructive pulmonary disease.
      ]. This finding likely reflects the effect of cumulative exposure to smoke and pollutants. Furthermore, telomere shortening, a distinctive sign of the aging process, characterizes COPD patients, and age and COPD additively promote it [
      • Savale L.
      • Chaouat A.
      • Bastuji-Garin S.
      • Marcos E.
      • Boyer L.
      • Maitre B.
      • et al.
      Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease.
      ]. Interestingly, telomerase dysfunction and the accelerated telomere shortening are also common in endothelial cells involved in the atherosclerotic process, a prototypal age-related condition, as well as in immunologic diseases, such as rheumatoid arthritis, which are strictly related to age [
      • Hohensinner P.J.
      • Goronzy J.J.
      • Weyand C.M.
      Telomere dysfunction, autoimmunity and aging.
      ,
      • Hoffmann J.
      • Spyridopoulos I.
      Telomere length in cardiovascular disease: new challenges in measuring this marker of cardiovascular aging.
      ]. Thus, a clear-cut biological basis seems to underlie the epidemiological evidence, although the link between COPD and defective telomerase should be depurated of the effects of previous infections such as Cytomegalovirus infection [
      • Spyridopoulos I.
      • Hoffmann J.
      • Aicher A.
      • Brümmendorf T.H.
      • Doerr H.W.
      • Zeiher A.M.
      • et al.
      Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity.
      ].
      Table 1COPD prevalence in selected European countries.
      CountryCOPD prevalenceReference populationData sourceYear
      Austria4.6%Adult population sampleStatistik Austria2007
      Belgium5.3%Middle-aged populationMinistry of Health. Health for all database2004
      Czech Republic2.4%Adult populationInstitute of Health — Information and Statistics2007
      FinlandOver 5% have diagnosed COPD; a further 5% estimated to have concealed COPDTotal populationThe National Finnish COPD Programme2007
      France6% to 8%Adult populationMinistère de la Santè et des Solidaritès2005
      Germany13.2%Adult populationGeldmacher et al. (BOLD study)
      • Geldmacher H.
      • Biller H.
      • Herbst A.
      • Urbanski K.
      • Allison M.
      • Buist A.S.
      • et al.
      The prevalence of chronic obstructive pulmonary disease (COPD) in Germany. Results of the BOLD study.
      2008
      Ireland7.3%Adult populationThe Irish Thoracic Society2008
      Italy4.5%Total populationISTAT2007
      Netherlands2%EstimatedNational Institute for Public Health and the Environment2006
      Portugal4.6%Adult populationNational Observatory of respiratory disease2008
      Serbia6.0%Adult populationInstitute of Public Health of Belgrade2007
      United Kingdom1.5% correctly diagnosed; 3.7 million (6%) estimated to be affectedPopulation over 40 years oldStang et al.
      • Stang P.
      • Lydick E.
      • Silberman C.
      • Kempel A.
      • Keating E.T.
      The prevalence of COPD: using smoking rates to estimate disease frequency in the general population.
      2000
      Several other similarities between aging lung and COPD lung are worth noting: vital capacity declines by 10–20 mL yearly in normal aging [
      • Lange P.
      • Parner J.
      • Schnohr P.
      • Jensen G.
      Copenhagen City Heart Study: longitudinal analysis of ventilatory capacity in diabetic and nondiabetic adults.
      ], about 30 mL in COPD patients [
      • Nishimura M.
      • Makita H.
      • Nagai K.
      • Konno S.
      • Nasuhara Y.
      • Hasegawa M.
      • et al.
      Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease.
      ], whereas residual volume increases in both normally aging and COPD lung [
      • Garcia-Rio F.
      • Dorgham A.
      • Pino J.M.
      • Villasante C.
      • Garcia-Quero C.
      • Alvarez-Sala R.
      Lung volume reference values for women and men 65 to 85 years of age.
      ]. Furthermore elastic recoil, mucociliary clearance, mucosal immunity and vascular reserve decrease in the elderly and, more, in COPD [
      • Lalley P.M.
      The aging respiratory system — pulmonary structure, function and neural control.
      ].
      Despite the strong link to age, COPD prevalence in the elderly is incompletely known. Indeed, both age-related changes in the clinical presentation of COPD and the confounding effect of comorbidity as well as several problems with the execution of spirometry contribute to hamper the diagnosis of COPD in the elderly population.

      3. Why COPD is often so difficult to diagnose in the elderly population?

      COPD is rarely presenting alone in elderly patients. Comorbidity and disability of various origins contribute to make the recognition of COPD problematic. Furthermore, cognitive impairment, mainly of verbal memory and constructive ability, and depression may dominate the clinical scene in subjects with hypoxemia and hypercapnia [
      • Incalzi R.A.
      • Gemma A.
      • Marra C.
      • Muzzolon R.
      • Capparella O.
      • Carbonin P.
      Chronic obstructive pulmonary disease. An original model of cognitive decline.
      ,
      • Antonelli-Incalzi R.
      • Corsonello A.
      • Trojano L.
      • Acanfora D.
      • Spada A.
      • Izzo O.
      • et al.
      Correlation between cognitive impairment and dependence in hypoxemic COPD.
      ]. Even severe exacerbations of COPD can be recognized late due to atypical presentation. Indeed, at variance with the classical triad of dyspnea, cough and fever [
      • Anthonisen N.R.
      • Manfreda J.
      • Warren C.P.
      • Hershfield E.S.
      • Harding G.K.
      • Nelson N.A.
      Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.
      ], muscle weakness, vertigo, confusion and leg edema, all reflecting severe hypoxemia, are the hallmark of atypical presentations [
      • Incalzi R.A.
      • Fuso L.
      • Serra M.
      • Basso S.
      • Carosella L.
      • Tramaglino L.M.
      • et al.
      Exacerbated chronic obstructive pulmonary disease: a frequently unrecognized condition.
      ], and occasionally delirium may be the main presenting feature. Age-related increase in the threshold of dyspnea and physical disability, frequently multifactorial in origin, variously contribute to make dyspnea a secondary feature of exacerbation in selected patients. Finally, chest pain may reflect right ventricular overload secondary to pulmonary hypertension or worsening myocardial ischemia by hypoxemia [
      • Incalzi R.A.
      • Fuso L.
      • Serra M.
      • Basso S.
      • Carosella L.
      • Tramaglino L.M.
      • et al.
      Exacerbated chronic obstructive pulmonary disease: a frequently unrecognized condition.
      ].
      Disability of non-respiratory origin, e.g. orthopedic or neurologic, can restrain physical activity at a level well below the threshold for dyspnea, hampering the recognition of stable COPD in the elderly. As a consequence, experience and skill are required to suspect and, then, diagnose COPD in the elderly.
      Spirometry plays a pivotal role in the diagnostic workup [
      • Celli B.R.
      • MacNee W.
      • ATS/ERS Task Force
      Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.
      ], but frail and disabled people may be unable to satisfactorily perform this test. Table 2 summarizes conditions more frequently accounting for a poor quality pulmonary function test [
      • Bellia V.
      • Pistelli R.
      • Catalano F.
      • Antonelli-Incalzi R.
      • Grassi V.
      • Melillo G.
      • et al.
      Quality control of spirometry in the elderly. The SA.R.A. study. SAlute Respiration nell'Anziano = Respiratory Health in the Elderly.
      ]. These factors contribute to the “epidemic” underdiagnosis of COPD: about half of patients with COPD escape recognition [
      • Bellia V.
      • Pistelli R.
      • Catalano F.
      • Antonelli-Incalzi R.
      • Grassi V.
      • Melillo G.
      • et al.
      Quality control of spirometry in the elderly. The SA.R.A. study. SAlute Respiration nell'Anziano = Respiratory Health in the Elderly.
      ]. Furthermore, the need of complying with spirometry criteria results in a biased selection of patients recognized as affected by COPD by automatically excluding the most frail. Indeed, subjects have to meet acceptability criteria of spirometry in at least three curves and, then, with repeatability criteria [
      • Lindberg A.
      • Bjerg A.
      • Rönmark E.
      • Larsson L.G.
      • Lundbäck B.
      Prevalence and underdiagnosis of COPD by disease severity and the attributable fraction of smoking. Report from the Obstructive Lung Disease in Northern Sweden Studies.
      ]. Table 3 displays the currently requested acceptability and reproducibility criteria, together with the corresponding technical index to determine quality control and the factors most commonly affecting the achievement of a good spirometric curve. Indeed, in the context of a study dedicated to spirometry for the elderly, the SaRA (Salute Respiratoria nell'Anziano = Respiratory Health in the Elderly) study, 4 out of 5 subjects over 64 with or without COPD could comply with acceptability criteria; cognitive impairment, poor physical performance and lower educational status characterized non-performers, while older age, male gender and severe bronchial obstruction were associated with unacceptable reproducibility [
      • Bellia V.
      • Pistelli R.
      • Catalano F.
      • Antonelli-Incalzi R.
      • Grassi V.
      • Melillo G.
      • et al.
      Quality control of spirometry in the elderly. The SA.R.A. study. SAlute Respiration nell'Anziano = Respiratory Health in the Elderly.
      ]. Interestingly, the volume of spirometries performed correlated positively with combined acceptability and reproducibility, stating that the experience of individual laboratory of respiratory pathophysiology contributes to the overall quality of the spirometry [
      • Miller M.R.
      • Hankinson J.
      • Brusasco V.
      • Burgos F.
      • Casaburi R.
      • Coates A.
      • et al.
      Standardisation of spirometry.
      ].
      Table 2Main conditions potentially affecting the quality of spirometry and, consequently, the achievement of a state of art COPD diagnosis in the elderly.
      Patient related conditions
      • Motor and sensory deficits, e.g. pyramidal or extra-pyramidal disorders

       – Lack of dexterity and poor control of ventilation during spirometry;

       – Difficulty in coordination and properly sequencing the flow volume maneuver and the breath holding.

      • Dementia or cognitive impairment: deteriorated constructive functions, verbal attainment and, mainly, secondary verbal memory

       – Difficulty in learning and recall instruction to perform spirometry

       – Poor ability to interact with the technician or physician

      • Mood depression and psychological factors

       – Poor motivation, early discouragement for unsuccessful trials.

      • Educational level

       – Ability to understand technical instructions

      • Malnutrition/undernutrition, deconditioning: respiratory muscles weakness

       – Difficulty in providing acceptable and reproducible tests
      Environment and technician related conditions
      • Poor geriatric expertise of the physician or technician

       – She/he is unable to teach the patient through a variety of non-verbal tools, like visual examples or touch-guided respiratory maneuver.

       – She/he does not motivate the proband by stressing any, even minimal, improvement, and does not tailor the teaching process to the individual learning potential.

      • Unpleasant or stressful environment

       – The diagnostic test does not fit the age-related slowing of learning process and, then, the need for gently repeated or even fractioned maneuvers.
      Table 3Factors limiting the achievement of acceptability and repeatability criteria in performing spirometry among elderly
      • Bellia V.
      • Pistelli R.
      • Catalano F.
      • Antonelli-Incalzi R.
      • Grassi V.
      • Melillo G.
      • et al.
      Quality control of spirometry in the elderly. The SA.R.A. study. SAlute Respiration nell'Anziano = Respiratory Health in the Elderly.
      .
      Acceptability criteria
      • Lalley P.M.
      The aging respiratory system — pulmonary structure, function and neural control.
      Quality controlLimiting factors in elderly
      Good start (no hesitation to begin the maneuver)• Extrapolated volume is <5% of FVC or 0.15 L, whichever is greater or

      • Time to PEF is <120 ms (optional until further information is available)
      • Motor and sensory deficit

      • Respiratory muscle weakness

      • Deconditioning
      Satisfactory and complete exhalation• 6 s of exhalation and/or a plateau in the volume–time curve or

      • Reasonable duration or a 1-second plateau in the volume–time curve or

      • The subject cannot or should not continue to exhale
      • Severe air trapping or airway obstruction

      • Restrictive lung disease

      • Poor motivation

      • Expiratory dyspnea
      Absence of artifacts• Cough or glottis closure during the first second of exhalation

      • Early termination or cutoff

      • Variable effort

      • Leak

      • Obstructed mouthpiece
      • Difficulty on learning and recall instruction to perform spirometry

      • Poor ability to interact with the technician
      At least three acceptable spirograms satisfying repeatability quality control criteria• Two largest FVCs within 0.2 L of each other

      • Two largest FEV1s within 0.2 L of each other
      • Respiratory muscles weakness or poor endurance

      • Physical unfitness and deconditioning

      • Poor motivation
      In an attempt at expanding the number of elderly people having a diagnostic spirometry, FEV6, i.e. the maximum volume of air expired at any time before the 6° s of the forced expiratory maneuver has been introduced and repeatedly tested. If the patient is unable to reach an end expiratory plateau ≥1 s, forced vital capacity (FVC) is not measurable, while FEV6 is. In Fig. 1 these differences are graphically represented. Accordingly, FEV1/FEV6 can substitute for FEV1/FVC. FEV6 has been proved to have good diagnostic properties for both obstructive and restrictive respiratory diseases [
      • Swanney M.P.
      • Jensen R.L.
      • Crichton D.A.
      • Beckert L.E.
      • Cardno L.A.
      • Crapo R.O.
      FEV(6) is an acceptable surrogate for FVC in the spirometric diagnosis of airway obstruction and restriction.
      ]. It also identifies smokers at risk of faster respiratory decline [
      • Enright R.L.
      • Connett J.E.
      • Bailey W.C.
      The FEV1/FEV6 predicts lung function decline in adult smokers.
      ]. The availability of reference standards, even for the elderly population, makes FEV6 of practical use [
      • Hankinson J.L.
      • Crapo R.O.
      • Jensen R.L.
      Spirometric reference values for the 6-s FVC maneuver.
      ,
      • García-Río F.
      • Pino J.M.
      • Dorgham A.
      • Alonso A.
      • Villamor J.
      Spirometric reference equations for European females and males aged 65–85 yrs.
      ]. Unfortunately, FEV6 is not a panacea: 440 out of the 1971 enrolled in the SaRA study could not perform spirometry (n = 101) or achieve a retrograde extrapolated volume <150 mL, i.e. did not achieve the requested explosive expiration [
      • Bellia V.
      • Sorino C.
      • Catalano F.
      • Augugliaro G.
      • Scichilone N.
      • Pistelli R.
      • et al.
      Validation of FEV6 in the elderly: correlates of performance and repeatability.
      ]. Thus, neither FVC nor FEV6 could be measured in 440/1971 probands. Furthermore, achievement and repeatability of FVC and FEV6 were defective in 262 and 186 people out of the 1531 who successfully performed spirometry respectively. Older age, a restrictive pattern, cognitive impairment and lower education were the main correlates of inability to achieve an acceptable and repeatable FEV6 (Fig. 1) [
      • Hankinson J.L.
      • Odencrantz J.R.
      • Fedan K.B.
      Spirometric reference values from a sample of the general U.S. population.
      ].
      Figure thumbnail gr1
      Fig. 1Spirometric representation, in a volume/time curve, of a maximal expiratory maneuver. Acceptability criteria for FVC and FEV6 are illustrated. Panel A: The proband achieved a good start and a complete exhalation. Thus, both FVC and FEV6 were measurable; panel B: Good start, but incomplete exhalation. FEV6, but not FVC could be measured; panel C: the maneuver lacked a good start and a complete exhalation. Neither FVC nor FEV6 could be measured.
      An additional diagnostic problem even for subjects able to perform spirometry is represented by the diagnostic criteria used. All the current guidelines use a reduction of the FEV1/FVC (or VC = slow vital capacity) as the hallmark for the diagnosis of bronchial obstruction. Reduction of FEV1/VC can be defined against a “fixed” cut-off (usually 0.7) or a lower limit of normal that corresponds to the 5th percentile of the theoretical distribution of the parameter in a healthy population of the same age, gender and body size. The former definition is recommended by the Global initiative against chronic Obstructive Lung Disease (GOLD), the latter by the ATS/ERS guidelines [
      • Celli B.R.
      • MacNee W.
      • ATS/ERS Task Force
      Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.
      ]. Both definitions have their drawbacks. On the one hand, the fixed cut-off does not take into account that FEV1 and VC do not decrease at the same rate with aging [
      • Hankinson J.L.
      • Odencrantz J.R.
      • Fedan K.B.
      Spirometric reference values from a sample of the general U.S. population.
      ]. As a consequence, a fixed cut-off tends to over-diagnose bronchial obstruction in elderly people. On the other hand, the lower limit of normal is calculated using predictive equations based on the assumption that the variability is proportional to the predicted values across ages; its validity also depends on the availability of standards developed in a reference normal population as similar as possible to the population under study. Both these assumptions are often unrealistic, especially in elderly people. The use of a lower cut-off in elderly people (0.65 and 0.67 in men and women, respectively) has been proposed and may overcome the shortcomings of the fixed cut-off and of the lower limit of normal [
      • Sorino C.
      • Battaglia S.
      • Scichilone N.
      • Pedone C.
      • Antonelli-Incalzi R.
      • Sherrill D.
      • et al.
      Diagnosis of airway obstruction in the elderly: contribution of the SARA study.
      ].
      Despite these limitations, spirometry remains the mainstay for the diagnosis of COPD and, broadly speaking, respiratory diseases at any age. Furthermore, it can provide important information on dynamic air trapping. i.e. on exercise-related decrease in inspiratory vital capacity due to increased expiratory reserve volume. Dynamic hyperinflation is a major correlate of dyspnea [
      • O'Donnell D.E.
      • Webb K.A.
      The major limitation to exercise performance in COPD is dynamic hyperinflation.
      ], and interventions able to limit it effectively prevent dyspnea [
      • Berton D.C.
      • Reis M.
      • Siqueira A.C.
      • Barroco A.C.
      • Takara L.S.
      • Bravo D.M.
      • et al.
      Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPD.
      ]. Thus, spirometry can guide the therapy besides allowing a correct diagnosis.
      Recently, efforts have been made at developing alternative diagnostic methods, but no solution has so far been made available. A very interesting and promising possibility is represented by the technology of the electronic nose that is an array of sensors that mimics the olfactory epithelium. It is based on six microbalance sensors covered with metalloporphyrins that upon interaction with volatile organic compound undergo frequency shifts that can be displayed as a sort of graphical breath print (Fig. 2). Such a technique has proved to have important diagnostic properties versus lung cancer, asthma and COPD [
      • Fens N.
      • Zwinderman A.H.
      • van der Schee M.P.
      • de Nijs S.B.
      • Dijkers E.
      • Roldaan A.C.
      • et al.
      Exhaled breath profiling enables discrimination of chronic obstructive pulmonary disease and asthma.
      ,
      • D'Amico A.
      • Pennazza G.
      • Santonico M.
      • Martinelli E.
      • Roscioni C.
      • Galluccio G.
      • et al.
      An investigation on electronic nose diagnosis of lung cancer.
      ]. Preliminary results available for elderly COPD patients are very encouraging [
      • Pennazza G.
      • Scarlata S.
      • Santonico M.
      • Chiurco D.
      • D'Amico A.
      • Incalzi R.A.
      Exhaled breath analysis for the monitoring of elderly COPD patients health-state.
      ]. The method is very easy, inexpensive, highly repeatable and safe [
      • Incalzi R.A.
      • Pennazza G.
      • Scarlata S.
      • Santonico M.
      • Petriaggi M.
      • Chiurco D.
      • et al.
      Reproducibility and respiratory function correlates of exhaled breath fingerprint in chronic obstructive pulmonary disease.
      ]. However, up to now the electronic nose should be considered a research tool. Large studies are needed to confirm its diagnostic and classificatory properties. Table 4 shows currently available evidence supporting the use of an electronic nose in lung diseases [
      • D'Amico A.
      • Pennazza G.
      • Santonico M.
      • Martinelli E.
      • Roscioni C.
      • Galluccio G.
      • et al.
      An investigation on electronic nose diagnosis of lung cancer.
      ,
      • Pennazza G.
      • Scarlata S.
      • Santonico M.
      • Chiurco D.
      • D'Amico A.
      • Incalzi R.A.
      Exhaled breath analysis for the monitoring of elderly COPD patients health-state.
      ,
      • Incalzi R.A.
      • Pennazza G.
      • Scarlata S.
      • Santonico M.
      • Petriaggi M.
      • Chiurco D.
      • et al.
      Reproducibility and respiratory function correlates of exhaled breath fingerprint in chronic obstructive pulmonary disease.
      ,
      • Mazzone P.J.
      Exhaled volatile organic compounds as biomarkers for respiratory diseases.
      ,
      • Dragonieri S.
      • Schot R.
      • Mertens B.J.A.
      • Le Cessie S.
      • Gauw S.A.
      • Spanevello A.
      • et al.
      An electronic nose in the discrimination of patients with asthma and controls.
      ,
      • Kanoh S.
      • Kobayashi H.
      • Motoyoshi K.
      Exhaled ethane. An in vivo biomarker of lipid peroxidation in interstitial lung diseases.
      ,
      • Fend R.
      • Kolk A.H.J.
      • Bessant C.
      • Buijtels P.
      • Klatser P.R.
      • Woodman A.C.
      Prospects for clinical application of electronic-nose technology to early detection of Mycobacterium tuberculosis in culture and sputum.
      ,
      • Dutta R.
      • Hines E.L.
      • Gardner J.W.
      • Boilot P.
      Bacteria classification using Cyranose 320 electronic nose.
      ,
      • Humphreys L.
      • Orme R.M.
      • Moore P.
      • Charaklias N.
      • Sahgal N.
      • Pont N.P.
      • et al.
      Electronic nose analysis of bronchoalveolar lavage fluid.
      ].
      Figure thumbnail gr2
      Fig. 2Seven-sensor response pattern registered by a Quartz micro balance based e-nose
      [
      • Enright R.L.
      • Connett J.E.
      • Bailey W.C.
      The FEV1/FEV6 predicts lung function decline in adult smokers.
      ]
      for four patients over 64 years (A: control; B: COPD Gold standard 1; C: COPD Gold standard 3; D: COPD Gold standard 4). The four fingerprints are reported in statistical terms (whiskers plot) because they average three measurements along a period of three weeks. Three pattern-types are evidently different in terms of profile and of dimensionality: A (ranging from 500 to 3500 Hz), B and C (ranging from 100 to 800 Hz), D (ranging from 300 to 1300 Hz).
      Table 4Diagnostic accuracy of volatile organic compounds fingerprint in the diagnosis of respiratory diseases.
      Lung cancerResults widely depend on the different sensor system used. Quartz microbalances currently show the best diagnostic accuracy around 90%. Sensitivity and specificity range from 70 to 90%
      • D'Amico A.
      • Pennazza G.
      • Santonico M.
      • Martinelli E.
      • Roscioni C.
      • Galluccio G.
      • et al.
      An investigation on electronic nose diagnosis of lung cancer.
      .
      AsthmaThe sensor system was able to separate mild asthmatics from controls, and moderate to severe asthmatics from controls, but not mild and moderate from severe asthmatic groups
      • Dragonieri S.
      • Schot R.
      • Mertens B.J.A.
      • Le Cessie S.
      • Gauw S.A.
      • Spanevello A.
      • et al.
      An electronic nose in the discrimination of patients with asthma and controls.
      .
      COPDBreath fingerprint was highly sensitive and specific in discriminating COPD patients from controls
      • Pennazza G.
      • Scarlata S.
      • Santonico M.
      • Chiurco D.
      • D'Amico A.
      • Incalzi R.A.
      Exhaled breath analysis for the monitoring of elderly COPD patients health-state.
      , hypoxemic from non-hypoxemic COPD
      • Incalzi R.A.
      • Pennazza G.
      • Scarlata S.
      • Santonico M.
      • Petriaggi M.
      • Chiurco D.
      • et al.
      Reproducibility and respiratory function correlates of exhaled breath fingerprint in chronic obstructive pulmonary disease.
      and COPD from asthma
      • Fens N.
      • Zwinderman A.H.
      • van der Schee M.P.
      • de Nijs S.B.
      • Dijkers E.
      • Roldaan A.C.
      • et al.
      Exhaled breath profiling enables discrimination of chronic obstructive pulmonary disease and asthma.
      ,
      • Mazzone P.J.
      Exhaled volatile organic compounds as biomarkers for respiratory diseases.
      Interstitial lung diseaseExhaled ethane seems a valuable indicator of disease activity and prognosis for ILDs
      • Kanoh S.
      • Kobayashi H.
      • Motoyoshi K.
      Exhaled ethane. An in vivo biomarker of lipid peroxidation in interstitial lung diseases.
      .
      Tuberculosis and other lung infectionsThe system was 89% sensitive and 91% specific at identifying M. tuberculosis
      • Fend R.
      • Kolk A.H.J.
      • Bessant C.
      • Buijtels P.
      • Klatser P.R.
      • Woodman A.C.
      Prospects for clinical application of electronic-nose technology to early detection of Mycobacterium tuberculosis in culture and sputum.
      . It was also able to differentiate several in-vitro gram + and gram − bacteria
      • Dutta R.
      • Hines E.L.
      • Gardner J.W.
      • Boilot P.
      Bacteria classification using Cyranose 320 electronic nose.
      . E-nose fingerprints correctly classified 77% of the BAL samples, with and without microbiological growth, from ventilated patients not on antibiotics. Inclusion of patients on antibiotics resulted in 68% correct classification. Seventy percent of isolates were accurately discriminated into four clinically significant groups
      • Humphreys L.
      • Orme R.M.
      • Moore P.
      • Charaklias N.
      • Sahgal N.
      • Pont N.P.
      • et al.
      Electronic nose analysis of bronchoalveolar lavage fluid.
      .
      Finally, asthma is not uncommon in the elderly and should be distinguished from COPD. Two types of asthma have been described in the elderly: an early onset form, which dates back to young adulthood and is easily recognized, even if it recurs after several years, and a late onset form. This latter form is frequently misclassified as COPD, and older age and disability are the main correlates of misclassification [
      • Bellia V.
      • Battaglia S.
      • Catalano F.
      • Scichilone N.
      • Incalzi R.A.
      • Imperiale C.
      • et al.
      Aging and disability affect misdiagnosis of COPD in elderly asthmatics: the SARA study.
      ]. Sputum eosinophilia and need of frequent steroid therapy may raise the suspect of asthma, but reversibility of the bronchial obstruction may be partial. Furthermore, based on a cluster analysis, a group of older obese women with late onset non-atopic asthma has been characterized as having moderate reductions in FEV1 and frequent exacerbations requiring oral corticosteroids [
      • Moore W.C.
      • Meyers D.A.
      • Wenzel S.E.
      • Teague W.G.
      • Li H.
      • Li X.
      • et al.
      Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program.
      ]. A tentative diagnostic algorithm is proposed in Table 5.
      Table 5A proposed diagnostic algorithm for asthma in the elderly.
      HistoryRespiratory function testsSupportive elements
      H1. Recurrent wheezeR1. Positive methacholine testS1. Early onset (in adolescence or young adulthood)
      H2. Nocturnal wheezeR2. Completely reversible bronchial obstructionS2. History of atopy
      H3. Dry cough (variant clinical presentation)R3. Partially reversible bronchial obstructionS3. Triggers identified
      S4. Sputum eosinophilia
      S5. Steroid dependence
      S6. Normal DLCO
      Proposed diagnostic criteria:
      A. H1 and/or H2 plus R1 and/or R2 (supportive elements unnecessary);
      B. H3 plus R1 and/or R2 (supportive elements unnecessary);
      C. Any combination of H and R3: one or more supportive elements (S1 to S6).

      4. How does COPD impact health status in old patients?

      COPD affects health status throughout all its natural history, but this effect becomes dramatic for FEV1 < 50% predicted [
      • Antonelli-Incalzi R.
      • Imperiale C.
      • Bellia V.
      • Catalano F.
      • Scichilone N.
      • Pistelli R.
      • et al.
      Do GOLD stages of COPD severity really correspond to differences in health status?.
      ]. Furthermore, even subjects who have not had their disease recognized suffer from noticeable health status impairment [
      • Coultas D.B.
      • Mapel D.
      • Gagnon R.
      • Lydick E.
      The health impact of undiagnosed airflow obstruction in a national sample of United States adults.
      ]. Loss of muscle mass, dyspnea, cognitive and affective disorders, osteoporosis and sleep troubles variously interact to impair personal independence and perceived health status [
      • Antonelli Incalzi R.
      • Pedone C.
      • Pahor M.
      Multidimensional assessment and treatment of the elderly with COPD.
      ]. A tentative synopsis of mechanisms affecting health status in COPD is provided in Fig. 3. It is also worth noting that the relationship between COPD course and health status may be to some extent reciprocal: for example, cognitive problems variously affect the adherence to the therapy (see Which are the main therapeutic problems in elderly COPD patients and which evidences are still lacking in this population? section), and sleep troubles may foster the improper use of respiratory depressant drugs [
      • Incalzi R.A.
      • Pedone C.
      • Onder G.
      • Pahor M.
      • Carbonin P.U.
      • GIFA
      Gruppo Italiano di Farmacovigilanza (Italian Group for Pharmacological Survey in the Elderly). Predicting length of stay of older patients with exacerbated chronic obstructive pulmonary disease.
      ]. Furthermore, depression is associated with persistent smoking and increased mortality [
      • Ng T.P.
      • Niti M.
      • Tan W.C.
      • Cao Z.
      • Ong K.C.
      • Eng P.
      Depressive symptoms and chronic obstructive pulmonary disease: effect on mortality, hospital readmission, symptom burden, functional status, and quality of life.
      ].
      Figure thumbnail gr3
      Fig. 3Synopsis of factors and interactions conditioning health status in the elderly COPD patient.
      These and other examples testify to the possibility that worsening health status further accelerates the progression of COPD. Thus, any effort should be made to interrupt this vicious circle.
      In the SaRA study, 31% of COPD patients had good health status, as reflected by physical and cognitive performance, affective status and quality of sleep, while 41% and 27% had moderately and severely deteriorated health status, respectively [
      • Antonelli-Incalzi R.
      • Imperiale C.
      • Bellia V.
      • Catalano F.
      • Scichilone N.
      • Pistelli R.
      • et al.
      Do GOLD stages of COPD severity really correspond to differences in health status?.
      ]. Variables exploring the physical domain, i.e. independence in activities assessed by the Barthel test and submaximal physical performance, were the main determinants of the health status pattern. Unexpectedly, the concordance between severity of airway obstruction and health status impairment was only moderate: 24.3% of patients with mild COPD had severely deranged health status, while 15.5% of those with severe COPD had fine health status. These findings caution against oversimplifying the relationship between bronchial obstruction and health status. Both phenotypic variability and comorbidity variously affect health status. For instance, dynamic hyperinflation, the phenomenon of exercise dependent air trapping, is associated with important dyspnea and, then, physical limitation [
      • O'Donnell D.E.
      • Revill S.M.
      • Webb K.A.
      Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease.
      ]. Social factors also contribute to health status and, in a special way, to the use of health care resources. The latter item is also relevant to the evolution of health status: it has been demonstrated that health status measurably declines after a hospital stay for exacerbated COPD [
      • Anzueto A.
      Impact of exacerbations on COPD.
      ]. Indeed, the rate of hospitalization of elderly people for exacerbated COPD is inversely related to the income; the same relationship has been demonstrated for other chronic conditions such as diabetes mellitus and congestive heart failure or for stroke, an acute condition deeply rooted in chronic conditions, but not for hip fracture [
      • Antonelli-Incalzi R.
      • Ancona C.
      • Forastiere F.
      • Belleudi V.
      • Corsonello A.
      • Perucci C.A.
      Socioeconomic status and hospitalization in the very old: a retrospective study.
      ]. Thus, even the optimal therapy should be supported by social interventions to improve health status.
      Measuring basic and instrumental activities of daily living (ADL and IADL) and selected measures of physical performance and analyzing their combinations allow verification that COPD affects personal independence in a distinctive way with regard to other chronic conditions such as congestive heart failure and diabetes mellitus [
      • Incalzi R.A.
      • Corsonello A.
      • Pedone C.
      • Corica F.
      • Carbonin P.
      • Bernabei R.
      • et al.
      Construct validity of activities of daily living scale: a clue to distinguish the disabling effects of COPD and congestive heart failure.
      ]. This difference extends also to needs of care: for instance, the combination of three physical limitations, e.g. in going around outside, climbing up or down the stairs and walking for at least 400 m, identifies patients with a longer stay for exacerbated COPD.

      5. What's about the prognosis of COPD?

      The overall prognosis of COPD is poor. The 3-year mortality in a COPD population without respiratory failure or other serious disease has been reported to be 23% [
      • Anthonisen N.R.
      • Wright E.C.
      • Hodgkin J.E.
      Prognosis in chronic obstructive pulmonary disease.
      ]. More recently, data from the TORCH (Towards a Revolution in COPD Health) trial on patients with average FEV1 of 44% showed a mortality of 15% in the placebo group [
      • Calverley P.M.
      • Anderson J.A.
      • Celli B.
      • Ferguson G.T.
      • Jenkins C.
      • Jones P.W.
      • et al.
      Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
      ]. Similar data came from the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) trial [
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ] that enrolled patients with comparable severity. The stratification of COPD severity is classically based on the degree of FEV1 reduction, although the most recent GOLD guidelines [
      From the global strategy for the diagnosis, management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD).
      ] also include frequency of exacerbations in their grading systems. In the elderly, however, a risk stratification only based on respiratory characteristics may be inadequate. In a population of COPD patients with a mean age > 65 years, mortality was best predicted by a composite index (the BODE index) including FEV1 along with nutritional status, exercise capacity, and dyspnea [
      • Celli B.R.
      • Cote C.G.
      • Marin J.M.
      • Casanova C.
      • Montes de Oca M.
      • Mendez R.A.
      • et al.
      The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease.
      ].
      The drawbacks of expressing FEV1 using predicted values (see above) also apply to risk stratification. Alternative ways of expressing FEV1, such as FEV1 divided by the height cubed, may be more appropriate in the elderly population [
      • Pedone C.
      • Scarlata S.
      • Scichilone N.
      • Forastiere F.
      • Bellia V.
      • Antonelli Incalzi R.
      Alternative ways of expressing FEV1 and mortality in an elderly population with and without COPD.
      ].
      A further major issue that needs to be taken into account with respect to prognosis is the heterogeneity of COPD itself. Beyond the classic distinction between the “bronchitic” and the “emphysematous” phenotype, different distinctive characteristics – such as responsiveness to bronchodilators, frequency of exacerbations, and presence of pulmonary hypertension – have been described that allow identifying different phenotypes with different prognoses. Phenotype heterogeneity likely underpins the highly variable rate of FEV1 decline observed in COPD patients [
      • Casanova C.
      • de Torres J.P.
      • Aguirre-Jaíme A.
      • Pinto-Plata V.
      • Marin J.M.
      • Cordoba E.
      • et al.
      The progression of chronic obstructive pulmonary disease is heterogeneous: the experience of the BODE cohort.
      ].
      Finally, comorbidity is a major prognostic factor in elderly COPD patients. A list of COPD-associated comorbidities is showed in Table 6. In a sample of 270 patients, mean (±SD) age 67 ± 9 years, followed up for 3.5 years, mortality was more strictly associated with chronic renal failure and coronary artery disease than with depressed FEV1 at baseline [
      • Antonelli Incalzi R.
      • Fuso L.
      • De Rosa M.
      • Forastiere F.
      • Rapiti E.
      • Nardecchia B.
      • et al.
      Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease.
      ]. However, age per se was the main negative predictor followed by EKG signs of right heart dysfunction: 6 year survival was 7% in patients with both a P wave consistent with right atrial overload and S1S2S3 (an S wave in D1, D2 and D3 leads), 18% if one of these signs was present and 36% in the absence of both, stating that the EKG effects of pulmonary hypertension mark a condition with a very poor prognosis [
      • Incalzi R.A.
      • Fuso L.
      • De Rosa M.
      • Di Napoli A.
      • Basso S.
      • Pagliari G.
      • et al.
      Electrocardiographic signs of chronic cor pulmonale: a negative prognostic finding in chronic obstructive pulmonary disease.
      ]. Neuropsychological dysfunction, as expressed by defective copying design, also contributes to worsen the prognosis [
      • Antonelli-Incalzi R.
      • Corsonello A.
      • Pedone C.
      • Trojano L.
      • Acanfora D.
      • Spada A.
      • et al.
      Drawing impairment predicts mortality in severe COPD.
      ], likely as a marker of damage of the deep brain, mainly the insula, secondary to hypoxemia and hypercapnia and ensuing autonomic dysregulation [
      • Royall D.R.
      Double jeopardy.
      ].
      Table 6Comorbid conditions classified according to their relationship with COPD *.
      Con-causal: sharing risk factors, mainly smokeCoexisting in the absence of shared risk factors, except for ageComplicating COPD
      Atherosclerotic disease: coronary, cerebral, lower limbsGlaucomaAnxiety/depression
      Chronic renal failureCognitive impairment
      Cognitive impairment may either complicate COPD or coexist with COPD, being degenerative or atherosclerotic in origin. It rarely complicates COPD in the absence of chronic hypoxemia.
      Cognitive impairment
      Cognitive impairment may either complicate COPD or coexist with COPD, being degenerative or atherosclerotic in origin. It rarely complicates COPD in the absence of chronic hypoxemia.
      Lung cancerDiabetes mellitusOsteoporosis
      Congestive heart failureBenign prostatic hypertrophySarcopenia
      Aortic aneurysmDegenerative joint diseaseArrhytmias
      Bladder cancerHypertensionDysphagia
      Pulmonary fibrosis (respiratory bronchiolitis–interstitial lung disease)Obstructive sleep apneaPulmonary embolism
      * The list of comorbidities is not exhaustive. It focuses on the conditions for which the available clinical and epidemiological evidence is more solid.
      a Cognitive impairment may either complicate COPD or coexist with COPD, being degenerative or atherosclerotic in origin. It rarely complicates COPD in the absence of chronic hypoxemia.
      In-hospital mortality also is affected by non-respiratory factors such as atrial fibrillation and ventricular arrhythmias [
      • Fuso L.
      • Incalzi R.A.
      • Pistelli R.
      • Muzzolon R.
      • Valente S.
      • Pagliari G.
      • et al.
      Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease.
      ]. Unfortunately, comorbidity, a conditio sine qua non of COPD in the elderly, has not been systematically collected and taken into consideration as a prognostic determinant in most of the studies.

      6. Which are the main therapeutic problems in elderly COPD patients and which evidences are still lacking in this population?

      Many problems affect the quality of therapy for COPD in elderly people:
      • 1)
        The source of information from pharmacological trials is intrinsically biased by selection criteria: 12 exclusion criteria are reported in the TORCH trial [
        • Calverley P.M.
        • Anderson J.A.
        • Celli B.
        • Ferguson G.T.
        • Jenkins C.
        • Jones P.W.
        • et al.
        Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
        ], 19 in the UPLIFT [
        • Tashkin D.P.
        • Celli B.
        • Senn S.
        • Burkhart D.
        • Kesten S.
        • Menjoge S.
        • et al.
        A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
        ] and 22 in the POET-COPD (Prevention of Exacerbations with Tiotropium in COPD) trial [
        • Vogelmeier C.
        • Hederer B.
        • Glaab T.
        • Schmidt H.
        • Rutten-van Mölken M.P.
        • Beeh K.M.
        • et al.
        Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
        ]. Comorbidity, cognitive impairment, depression and physical limitations, which are the hallmark of COPD in the elderly, are among the most recurrent exclusion criteria. For instance, the means of participants in these trials were 65 years (range 40–80; SD 8.2) for TORCH, 65 years (SD 8.0) for UPLIFT, and 63 (SD 9.0) for POET-COPD. As a consequence, trial-based information “may not” apply to the average elderly COPD patient, the one we daily care for in our wards and ambulatories.
      • 2)
        Inhaler devices, seemingly simple to use, may be quite demanding for an elderly COPD patient. Indeed, coordination and respiratory muscle strength are variously required to correctly inhale the drug. It has been proved that cognitive impairment dramatically impacts the ability to correctly use the inhalers: scoring less than 24 on the Mini-Mental State Examination (MMSE) test, a simple screening instrument, is associated with a very high risk of failure [
        • Board M.
        • Allen S.C.
        A simple drawing test to identify patients who are unlikely to be able to learn to use an inhaler.
        ]; even an abnormal pentagon copying test, a component of the MMSE assessing constructive ability, identifies patients unable to use inhaler devices (Fig. 4). The adherence to both pharmacological and non-pharmacological therapy is frequently poor in the presence of cognitive impairment. Either a screening test, such as the MMSE, or a confirmatory neuropsychological assessment, like the Mental Deterioration Battery, or a test of secondary memory, e.g. the Rey's fifteen word test, successfully identifies COPD patients at risk of poor compliance [
        • Incalzi R.A.
        • Gemma A.
        • Marra C.
        • Capparella O.
        • Fuso L.
        • Carbonin P.
        Verbal memory impairment in COPD: its mechanisms and clinical relevance.
        ,
        • Carlesimo G.A.
        • Caltagirone C.
        • Gainotti G.
        The Group for the Standardization of the Mental Deterioration Battery
        The Mental Deterioration Battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment.
        ,
        • Rey A.L.
        Examen clinique en psychologie.
        ].
        Figure thumbnail gr4
        Fig. 4Mini-Mental State Examination test: the two pentagons copy figure for the evaluation of constructive ability. A defective performance targets elderly patients at risk of misuse of inhalation devices.
      • 3)
        Repeated rehabilitation can dramatically slow the decline of health status and decrease the need of health care as well as improve COPD-related mood disorders [
        • Alexopoulos G.S.
        • Sirey J.A.
        • Raue P.J.
        • Kanellopoulos D.
        • Clark T.E.
        • Novitch R.S.
        Outcomes of depressed patients undergoing inpatient pulmonary rehabilitation.
        ,
        • Foglio K.
        • Bianchi L.
        • Bruletti G.
        • Porta R.
        • Vitacca M.
        • Balbi B.
        • et al.
        Seven-year time course of lung function, symptoms, health-related quality of life, and exercise tolerance in COPD patients undergoing pulmonary rehabilitation programs.
        ]. Based on these evidences, depressed and disabled patients should be considered for and not excluded from rehabilitation programs. These beneficial effects are also evident in older [
        • Sewell L.
        • Singh S.J.
        • Williams J.E.
        • Collier R.
        • Morgan M.D.
        Can individualized rehabilitation improve functional independence in elderly patients with COPD?.
        ] and severely diseased patients [
        • Carone M.
        • Patessio A.
        • Ambrosino N.
        • Baiardi P.
        • Balbi B.
        • Balzano G.
        • et al.
        Efficacy of pulmonary rehabilitation in chronic respiratory failure (CRF) due to chronic obstructive pulmonary disease (COPD): the Maugeri study.
        ], but rehabilitation remains under-prescribed [
        • Di Meo F.
        • Pedone C.
        • Lubich S.
        • Pizzoli C.
        • Traballesi M.
        • Incalzi R.A.
        Age does not hamper the response to pulmonary rehabilitation of COPD patients.
        ].
      • 4)
        Many problems characterize this patient and require dedicated care to minimize her/his sufferance (suffering) and to help relatives and caregivers [
        • Corsonello A.
        • Pedone C.
        • Incalzi R.A.
        Clinical and prognostic implications of cognitive dysfunction and depression in COPD.
        ]. Unfortunately, at variance from palliative care for the neoplastic patient, palliative care for the respiratory patient, is poorly available and less perceived as an important health need [
        • Yohannes A.M.
        Palliative care provision for patients with chronic obstructive pulmonary disease.
        ]. The few available experiences show that providing at home palliative care is quite demanding and poses important organization problems [
        • Horton R.
        • Rocker G.
        • Dale A.
        • Young J.
        • Hernandez P.
        • Sinuff T.
        Implementing a palliative care trial in advanced COPD: a feasibility assessment (the COPD IMPACT study).
        ]. For a comprehensive overview of the subject, the reader is referred to the state of art review by Halpin and colleagues [
        • Halpin D.M.G.
        • Seamark D.A.
        • Seamark C.J.
        Palliative and end-of-life care for patients with respiratory disease.
        ].
      • 5)
        Elderly COPD patients are exposed to an important risk of adverse drug reactions due to overdosage of drugs with renal clearance. Indeed, sarcopenia, a common trait of severe COPD, blunts the creatinine rise due to depressed glomerular filtration rate. Thus, moderate (GFR = 60–30) and even severe renal failure may remain unrecognized [
        • Incalzi R.A.
        • Corsonello A.
        • Pedone C.
        • Battaglia S.
        • Paglino G.
        • Bellia V.
        Extrapulmonary Consequences of COPD in the Elderly Study Investigators
        Chronic renal failure: a neglected comorbidity of COPD.
        ]. This problem can emerge in the occasion of acute exacerbation requiring antibiotics or chronically for non-respiratory drugs and also for some topic bronchodilators which are fractionally adsorbed and cleared by the kidney.
      • 6)
        Polypathology and inherent polypharmacy is the rule in the elderly COPD patient [
        • Paladini L.
        • Hodder R.
        • Cecchini I.
        • Bellia V.
        • Incalzi R.A.
        The MRC dyspnoea scale by telephone interview to monitor health status in elderly COPD patients.
        ]. It is frequently unclear to which extent guidelines for individual diseases apply to such a complex patient. For example, beta-blockers for coexisting CHF have historically been considered to worsen bronchial obstruction in COPD, whereas they are currently contraindicated in asthma, but not in COPD [
        • Andrus M.R.
        • Holloway K.P.
        • Clark D.B.
        Use of beta-blockers in patients with COPD.
        ]. Furthermore, highly prevalent comorbidities can dramatically impact the respiratory function; for example, osteoporosis can account for vertebral fractures and, then, a restrictive component of the respiratory dysfunction [
        • Schlaich C.
        • Minne H.W.
        • Bruckner T.
        • Wagner G.
        • Gebest H.J.
        • Grunze M.
        • et al.
        Reduced pulmonary function in patients with spinal osteoporotic fractures.
        ]. Analogously, obstructive sleep apnea syndrome, which is very common but has atypical presentations in the elderly [
        • Endeshaw Y.
        Clinical characteristics of obstructive sleep apnea in community-dwelling older adults.
        ], can directly affect the respiratory function. The screening, assessment and treatment of comorbidities in COPD patients are therefore a pivotal approach deserving systematic attention by clinicians.
      • 7)
        Hypercatabolism and accelerated loss of muscle mass characterize severe exacerbations of COPD, but they also are a sort of phenotypic trait of an important fraction of COPD patients. Thus, attempts at treating promptly the exacerbation, so that the inflammatory response ceases, and providing nutritional support and rehabilitation are key issues in the treatment of exacerbated COPD. Nutritional interventions could improve both respiratory and peripheral muscle strength, but not respiratory function indexes [
        • Collins P.F.
        • Elia M.
        • Stratton R.J.
        Nutritional support and functional capacity in chronic obstructive pulmonary disease: a systematic review and meta-analysis.
        ]. As for very frail and disabled geriatric patients [
        • Fiatarone M.A.
        • O'Neill E.F.
        • Ryan N.D.
        • Clements K.M.
        • Solares G.R.
        • Nelson M.E.
        • et al.
        Exercise training and nutritional supplementation for physical frailty in very elderly people.
        ], a comprehensive intervention program, mainly based on exercise and nutritional support, seems worth testing.

      7. How should the physicians approach the elderly COPD patient? Does the real world approach change as a function of specialty?

      While guidelines for the treatment of COPD, mainly GOLD, NICE, and ATS/ERS, have been produced and disseminated in the last ten years, the approach to COPD has been reported to vary as a function of the physician's specialty [
      • Paladini L.
      • Hodder R.
      • Bellia V.
      • Marchionni N.
      • Di Bari M.
      • Cecchini I.
      • et al.
      Physician specialty as a source of heterogeneity in the care of patients with COPD.
      ]. It has been reported that both geriatricians and pulmonologists conform to a specialty-specific approach to COPD, whereas internists are characterized by a great variety of approaches [
      • Paladini L.
      • Hodder R.
      • Bellia V.
      • Marchionni N.
      • Di Bari M.
      • Cecchini I.
      • et al.
      Physician specialty as a source of heterogeneity in the care of patients with COPD.
      ]. Interestingly, the comprehensive approach to the health status is the hallmark of the geriatrician's approach, while the attention to phenotypic heterogeneity of COPD is that of the pulmonologist's approach. Indeed, multidimensional assessment is common practice for the geriatrician, whereas pulmonologists pay attention to clinical implications of dynamic hyperinflation. Since both approaches are highly motivated for the elderly COPD patient, it seems desirable to combine elements of both in order to improve the quality of care.
      Unfortunately, the most widely used guidelines (GOLD, NICE, and ATS/ERS) neither refer to specific issues of interest for the elderly nor underline the distinctive features of COPD in this large subset of patients. Indeed, only in their last version recently GOLD guidelines have started to mention comorbidity [
      From the global strategy for the diagnosis, management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD).
      ] In addition, the ATS/ERS guideline on rehabilitation partly addressed these topics when considering depression and anxiety [
      • Bakke P.S.
      Comorbidities in current COPD guidelines.
      ].

      8. Conclusions

      COPD is a “blanket” definition for a very heterogeneous disease. Older age adds to this heterogeneity mainly in terms of atypical presentation, confounding by comorbidity and poor knowledge of age-related changes in responsiveness to therapy proved useful in adult populations. Efforts should be made to provide respiratory function standards really valid for the elderly as well as to make the diagnostic procedures suitable for the vast majority of the elderly patients so that also frail and disable people be screened and diagnosed to have or not to have COPD. Clinical trials should be rethought to include frail people and, thus, generate real world results. The overall approach to these patients should ideally share expertise and skills from different specialties to provide a comprehensive approach to a multifaceted disease. However, preliminary and introductory to these actions is the spreading of awareness of COPD as a major health and social problem by the public opinion and political authorities. Indeed, chronic non-communicable diseases like ischemic heart disease or diabetes mellitus are correctly perceived as a dramatic burden for our societies, while the same is not true for COPD, despite the clear epidemiological evidence [
      • Miravitlles M.
      • Murio C.
      • Guerrero T.
      • Gisbert R.
      Costs of chronic bronchitis and COPD: a 1-year follow-up study.
      ]. Knowledge precedes and motivates action: the well evident diagnostic and therapeutic difficulty with COPD in the elderly will probably wane only if COPD will be correctly perceived in its true prevalence, complexity and changing features with aging. Internists, who care for the majority of elderly COPD patients, are strongly committed to pursue this objective.

      Learning points

      • COPD is highly prevalent, but it frequently remains unrecognized in the elderly due to atypical presentation and confounding by comorbidity.
      • A relevant proportion of elderly people cannot perform a satisfactory spirometry, i.e. a spirometry meeting both quality and repeatability criteria. This further makes a gold standard diagnosis of COPD problematic.
      • COPD dramatically impacts health status of elderly patients, but an optimal and multidimensional treatment can significantly limit this effect.
      • Comorbidity has a major prognostic role, but selected comorbidity, e.g. chronic renal failure and coronary artery disease, frequently remains unrecognized.
      • Therapeutic recommendations coming from large scale trials only partly apply to the elderly patient, because they have been obtained on populations which are poorly representative of the real world elderly population.
      • The internists, who care for the majority of elderly COPD patients, should aim at integrating components of approach to COPD by different specialties in order to provide a truly comprehensive and effective treatment.

      Conflict of interests

      The authors have no conflicts of interests to declare related to this manuscript.

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