Obstructive lung diseases at an outpatient clinic: Phenotypes and non-pharmacological treatment outcomes - Thesis

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Obstructive lung diseases at an outpatient clinic

Phenotypes and non-pharmacological treatment outcomes

Rootmensen, G.N.

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2020

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Rootmensen, G. N. (2020). Obstructive lung diseases at an outpatient clinic: Phenotypes and

non-pharmacological treatment outcomes.

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phenotypes and non-pharmacological treatment outcomes

Geert N. Rootmensen

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539054-L-bw-Rootmensen 539054-L-bw-Rootmensen 539054-L-bw-Rootmensen 539054-L-bw-Rootmensen Processed on: 30-1-2020 Processed on: 30-1-2020 Processed on: 30-1-2020

Processed on: 30-1-2020 PDF page: 1PDF page: 1PDF page: 1PDF page: 1

Obstructive lung diseases at an outpatient clinic:

phenotypes and non-pharmacological

treatment outcomes

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isbn: 978-94-6402-073-1 drukker: Gildeprint

layout: Guus Gijben ontwerpomslag: Martin van Triest

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Obstructive lung diseases at an outpatient clinic:

phenotypes and non-pharmacological treatment outcomes

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus

prof. dr. ir. K.I.J. Maex

ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel

op dinsdag 3 maart 2020, te 10.00 uur

door

Geert Nico Rootmensen

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Promotores: prof. dr. P.J. Sterk AMC-UvA prof. dr. R.J. de Haan AMC-UvA

Copromotor: dr. A.R.J. van Keimpema AMC-UvA

Overige leden: prof. dr. E.H.D. Bel AMC-UvA prof. dr. W.J.M. Scholte op Reimer AMC-UvA prof. dr. M.A.G. Sprangers AMC-UvA

prof. dr. J.W.M. Muris Universiteit Maastricht prof. dr. J.A.M. van der Palen Universiteit Twente

dr. C.J. Majoor AMC-UvA

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Chapter 1

General introduction and

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Obstructive Lung Diseases: Asthma and Chronic Obstructive

Pulmonary Disease

History

Obstructive lung diseases like asthma and chronic obstructive pulmonary disease (COPD) have a long historic background. The term asthma derives from the Greek verb aazein, meaning to pant, to exhale with open mouth, sharp breath.

The earliest text in which the term asthma is used as a medical term was in the

Corpus Hippocraticum by Hippocrates. It is unclear if Hippocrates (ca 460-370 BC)

meant asthma as a clinical entity or merely as a symptom. In 1860, Henry Hyde Salter, who suffered from asthma himself, refined the definition of asthma in his opus “On Asthma: Its Pathology and Treatment”. In this work he defined asthma as “Paroxysmal dyspnoea of a peculiar character with intervals of healthy respiration between attacks” (1). It describes the concept of periodic airway smooth muscles contraction which leads to narrow airways and causing shortness of breath. This is a typical feature of asthma.

In 1846, Hutchinson invented the spirometer, a key instrument in the diagnosis and management of asthma and COPD. It took another century before Tiffeneau added the concept of timed vital capacity as a measure of airflow so that the spirometer could be used as a diagnostic instrument (2), meaning the degree of bronchial obstruction could be defined.

Asthma and COPD are the two most well-known obstructive airway disorders. Both disorders have a considerable impact on patients’ daily functioning and that of their families.

The first attempt to define COPD was made at the Ciba symposium in 1958 (3). In 2001, the Global Initiative of Obstructive Lung Disease (GOLD) was launched by the World Health Organisation (WHO) and National Heart, Lung, and Blood Institute (NHLBI) (4). The GOLD criteria offered a new classification of the severity of COPD. Since its introduction, the GOLD criteria have been frequently updated and globally accepted (https://goldcopd.org/). Specifically, COPD is defined as a common, preventable and treatable disease that is characterised by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. The most commonly encountered risk for COPD is tobacco smoking.

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Regarding asthma, the classification developed by the Global Initiative on Asthma (GINA) is the most widely used. This report were first published in 1995 in collaboration with the NHLBI and WHO and has been updated frequently (https:// ginasthma.org/gina-reports/). By definition, asthma is considered a heterogeneous disease, usually characterised by chronic airway inflammation. The first effort of the GINA report was the production of a consensus on asthma treatment, which aimed to bridge the gap between the various treatment options, the incorporation and implementation of innovative treatment forms into daily clinical practice.

In the Netherlands, from 1961 until the beginning of the 1990s, disease entities such as asthma, chronic bronchitis and emphysema were considered ‘different patterns of the same disease’. They were named ‘chronic non-specific lung disease’ (in Dutch:

chronisch aspecifieke respiratoire aandoening, abbreviated CARA) (5). This so-called

Dutch hypothesis assumed that both asthma and COPD shared a common genetic root and had similar pathophysiological characteristics and clinical manifestations (5, 6). Until now, the underlying pathophysiology for the complex diseases asthma and COPD remains largely unknown and the common genetic root postulated in the Dutch hypothesis has never been established in genome-wide association studies (GWASs) (7). Although the common genetic root has never been proven, the concept from Orie and Sluiter not to place a single disease label on a patient (i.e. asthma or chronic bronchitis) is now considered accurate. Currently, phenotyping of patients is of increasing importance and many experts endorse the original theory of Orie and Sluiter.

Asthma definition

Definition of asthma from GINA guidelines 2019

(aug 2019 https://ginasthma.org/gina-reports/)

Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and intensity, together with variable expiratory airflow limitation.

The number of individuals with asthma is estimated at 300 million worldwide. Asthma still imposes an unacceptable burden on health care systems and on society through the loss of productivity in the workplace, and contributes to many deaths worldwide.

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Asthma is a chronic inflammatory disease of the airways, characterised by variable airflow obstruction, which is reversible either spontaneously or with treatment. It is associated with variable complaints of airway hyper-responsiveness and symptoms of chronic cough, wheeze, chest tightness and sputum production. Factors that may trigger or worsen asthma symptoms include viral infections, domestic or occupational allergens (e.g. house dust mite, pollens, cockroach), tobacco smoke, exercise and stress. In addition, some drugs such as aspirin, beta-blockers or NSAIDs (non-steroid anti-inflammatory drugs) can induce or trigger asthma. Asthma can be a fatal disease in case of an exacerbation (or flare up, attack). Exacerbations are more common and more severe in some high-risk patients or when asthma is uncontrolled. The disease affects people of all ages, has genetic components and its spectrum ranges from mild intermittent to severely disabling when uncontrolled. The diagnosis is often made based upon the symptoms and the evidence of variable airflow limitation. Episodic airway obstruction, which is characterised by variable, expiratory airflow limitation, often responsive to bronchodilators (increase of FEV1 ≥ 12%and ≥200 ml), represents the main physiological feature of asthma. Airway hyper-responsiveness diagnosed by inhaled methacholine or histamine also favours the diagnosis of asthma. Asthma is likely caused by gene-environment interaction, which may vary between inception at young and older ages (8). Several genetic loci have been associated with asthma, which seem to interact with exposures such as virus infections, allergen exposure and other external factors ‘hitting’ the airways (9).

COPD definition

Definition of COPD from GOLD 2019

(aug 2019 https://goldcopd.org/)

Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. The chronic airflow limitation that is characteristic of COPD is caused by a mixture of small airways disease (e.g., obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person.

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COPD represents an important public health challenge and is a major cause of preventable chronic morbidity and mortality throughout the world. COPD is currently the fourth leading cause of death in the world (10, 11) but is projected to be the third leading cause of death by 2020. More than 3 million people died of COPD in 2012 accounting for 6% of all deaths globally. Globally, the COPD burden is projected to increase in coming decades because of continued exposure to COPD risk factors and ageing of the population (12).

COPD is a collective term for chronic bronchitis, pulmonary emphysema and peripheral airway disease that is associated with abnormal inflammatory response to noxious particles or gases, of which cigarette smoke is the most important. Besides cigarette smoke, COPD can also be caused by occupational exposure to dust or fumes and indoor biomass fuel cooking in developing countries (13, 14). Genetic mutations (e.g. alfa1-antitrypsin deficiency) can also cause COPD emphysema and are likely involved in several other phenotypes of the disease. Although largely preventable, COPD is one of the major causes of chronic morbidity and mortality (11). Quitting smoking and early, correct diagnosis is essential for treatment and prevention of further damage. COPD is characterised by airway obstruction that typically progresses over years and is not fully reversible. COPD diagnosis requires lung function testing with a ratio of post bronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity below 0.7. Other characteristics, such as age of over 40, cumulative smoking history, symptoms of cough, sputum production and dyspnoea can contribute to the diagnosis of COPD. The goals of COPD assessment are to determine the severity of the disease, including the severity of airflow limitation, the impact of disease on the patient’s health status and the risk of future events (such as exacerbations, hospital admissions, or death), and to guide therapy.

Phenotypes of Obstructive Lung Diseases

Although there is international consensus about the definitions of asthma and COPD, the complexity of these diseases is clearly apparent from the need to combine so many features and characteristics in defining them. The diagnoses of these obstructive lung diseases are not mutually-exclusive and classification of day-to-day patients into such specific disease entities has shown to be difficult (15-18).

Indeed, there appears to be an overlap between different phenotypes of obstructive lung diseases because patients often share characteristics of both entities. This has led to attempts to define different overlapping phenotypes of obstructive lung disease by even defining a new disease entity or syndrome: Asthma COPD Overlap Syndrome (ACOS) (19). Such overlapping phenotypes can be derived from clinical assessment

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and (better) by statistical approaches, such as cluster analysis. Cluster analysis is a validated approach to describe different patterns of patient groups based on clinical, physiological and biological features of obstructive lung diseases and can be used for defining subgroups of individuals. Recognition of different phenotypes within obstructive lung diseases is not only important for understanding the underlying disease processes but is also clinically relevant due to potentially different responses to therapeutic interventions (15, 20, 21). A majority of cluster analysis studies have been performed using carefully prepared patient selections with strict inclusion and exclusion criteria, with some being performed on population samples (22) or unselected patient populations (23). However, exclusion of specific patients decreases the reliability of achieving a representative classification of different phenotypes as encountered in clinical practice like e.g. an outpatient clinic.

Recently, the GINA and GOLD issued a joined document (available at https://goldcopd. org/wp-content/uploads/2016/04/GOLD-2018-WMS.pdf) that describes ACOS as a clinical disease entity and suggests that physicians should compile the features for asthma and for COPD that best describe the patient and compare the number of features in favour of each diagnosis. If similar features of asthma and COPD are present, the diagnosis ACOS can be considered. Interestingly, even more advanced, it has recently been advocated to place emphasis on treatable characteristics rather than the traditional diagnosis of asthma, COPD and even ACOS in the management of patients with chronic airways disease (24). This latter development brings ‘personalised’ or ‘precision’ medicine to the clinic by tailoring the assessment and management to the individual patient.

Treatment of Obstructive Lung Diseases

Amongst other diseases, treatment of asthma in ancient Egypt has been described in the Georg Ebers papyrus, found in the 1870s. One of the ancient Egyptian remedies was to heat a mixture of herbs on bricks and inhale their fumes. A few hundred years ago, it was common in China to give a person with asthma herbs containing ephedrine through which they were exposed to beta agonist activity. At the beginning of the 20th century, asthma was considered a psychosomatic disease and was considered by Franz Alexander, a Hungarian-American psychoanalyst and physician, as one of the “holy seven” psychosomatic diseases. Accordingly, a child’s wheeze was seen as a suppressed cry for his or her mother. Psychoanalysts thought that patients with asthma should be treated for depression with psychoanalysis. This psychoanalytic theory has been refuted.

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13 Figur e 1: Pharmacological tr eatment asthma ( GINA strategy r eport 201 9) ©201 9 G lobal I nitiativ e for Asthma, a vailable fr om www .ginasthma. or g, r eprinted with permission

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Perspectives have changed drastically. Since the 1960s, asthma has been considered an inflammatory disease with medical treatment primarily focusing on anti-inflammatory medication. The long-term goals of asthma management are to achieve good symptom control and to minimise future risk of exacerbations, fixed airflow limitation and side-effects of treatment. The patient’s own goals regarding treatment should also be identified.

Pharmacologic treatment

Depending on the severity of the disease, a stepwise pharmacological treatment is chosen for asthma patients (Figure 1).

At step 1, treatment is with as-needed inhaled corticosteroids (ICS)/formoterol. Treatment with regular daily low-dose of inhaled corticosteroids is highly effective in reducing asthma symptoms and reducing the risk of asthma-related exacerbations, hospitalisations and deaths. For patients with persistent symptoms or exacerbations, the preferred step-up treatment in step 2-4 is the combination of ICS/ long-acting beta2-agonist (LABA). Other options in the treatment of asthma are anticholinergic medication, leukotriene receptor antagonists (LTRA) or theophylline. In step 5, treatment of add-on medication, such as anti-immunoglobulin E (anti-IgE), anti-interleukins 5 (anti-IL5), a long-acting muscarinic antagonist (LAMA) or oral steroids, can be considered. If asthma is well controlled, a step down in treatment can be considered.

Pharmacologic treatment of COPD is used to reduce both symptoms and the frequency and severity of exacerbations as well as improve exercise tolerance and health status. In the latest revised COPD assessment, patients should undergo spirometry for the assessment of the airflow limitation (i.e. spirometric grade of COPD). To understand the impact of their COPD, patients should also undergo assessment of their dyspnoea symptoms using the mMRC or CATTM_{scale and their} history of exacerbations. Using this tool, patients can be categorised in group A,B,C or D (Figure 2).

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15 Figure 2: Assessment of COPD (COPD GOLD report 2019)

Individualised decisions on initial pharmacologic approaches can be used in the pharmacological recommendation (Figure 3). Following implementation of the therapy, patients should be reassessed for attainment of treatment goals and identification of any barriers for successful treatment. Following review of the patient response to treatment initiation, adjustment in pharmacological treatment may be needed (Figure 4). In the follow-up treatment of patients with COPD, recommendations are made based upon treatable traits symptoms and exacerbations. Recommendations do not depend on the patient’s GOLD group at diagnosis (Figure 5).

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Figure 3: Initial pharmacological treatment COPD (COPD GOLD report 2019)

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17 Figure 5: Follow-up pharmacological treatment COPD (COPD GOLD report 2019)

Inhaled bronchodilators in COPD are central to symptom management and commonly given on a regular basis to prevent or reduce symptoms. Bronchodilators act by altering airway smooth muscle tone and the improvement in expiratory flow reflects a widening of the airways rather than changes in elastic recoil, which tends to reduce dynamic hyperinflation at rest and during exercise (25, 26) and improve exercise performance. The role of ICS is less prominent as in the treatment of asthma. In vivo data suggest that the dose-response relation and long-term (>3

years) safety of ICS in patients are unclear and require further investigation (27). In the GLUCOLD study it was found that ICS therapy decreases inflammation and can attenuate decline in lung function in s teroid-naive patients with moderate to severe COPD (28). Analysis of this study population showed that CD163+ macrophages in bronchoalveolar lavage (BAL) fluids correlates with decrease in lung function

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suggesting that there is an anti-inflammatory phenotype. Prospective studies are required to show whether inflammatory treatment contributes to the anti-inflammatory macrophage phenotype in vivo, and whether this contributes to

treatment effects on inflammation and clinical outcomes such as lung function decline (29). In a meta-analysis, treatment with an ICS alone in COPD patients do not modify the long-term decline of FEV1 nor reduce mortality (30). In patients with moderate to very severe COPD and exacerbations, an ICS combined with a LABA is more effective than either component alone in improving lung function, health status and reducing exacerbations (31, 32). Clinical trials, however, failed to demonstrate a significant effect of combination therapy on survival (33, 34). Although oral steroids have a role in the treatment of acute exacerbations of COPD, they have no role in the chronic treatment of patients with COPD because of a lack of benefit balanced against the high rate of systemic complications. Other oral drugs, such as mucolytic medication, antioxidant agents, continuous antibiotics and phosfodiesterase-4 (PDE4) inhibitors, may have beneficial effects for selected patients with COPD. Influenza causes significant morbidity and mortality, and annual vaccination against influenza is advised for patients with asthma and COPD since it can reduce serious illness (e.g. lower airway tract infections requiring hospitalisation) (35) and death in COPD patients (36). Pneumococcal vaccinations PCV13 and PPSV23 are recommended for all patients ≥65 years of age. The PPSV23 is also recommended for younger COPD patients with significant co-morbid conditions, including chronic heart of lung disease (37). In contrast, for patients with asthma, there is insufficient evidence to recommend routine pneumococcal vaccination (38).

Non-pharmacological treatment

In addition to pharmacological treatment, non-pharmacological treatments are important in patients with chronic obstructive lung disease. As stated above, inhalation medication is the cornerstone in the pharmacological treatment for patients with obstructive lung diseases, whereby training of inhalation skills is considered as an important non-pharmacological intervention. Both GINA and GOLD guidelines emphasise the importance of skills training in device technique on a regular basis, as there is a relation between poor inhalation technique and poor symptom control (39, 40). On average, more than two-thirds of patients make at least one error in using an inhalation device (40-42). Inhalation devices include nebulisers, metered-dose inhalers (MDIs) used with or without a spacer, soft-mist inhalers, breath actuated MDIs (BAIs) and single-dose and multi-dose dry powder inhalers (DPIs). Skills training is advised to use inhalers effectively, and this is best achieved when there is a good partnership between the patient and their health care

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provider. Notably, randomised controlled trials have not identified superiority of one device/formulation (43). However, it needs to be stated that patients included in these trials are usually those who master inhalation technique and receive proper education and may not reflect the normal practice of an outpatient clinic. Moreover, the assessment methods of inhalation technique in most trials have not been validated. Despite the importance of correct inhalation technique, there is insufficient information about determinants that could affect inhalation technique, including age, type of device, education level or intensity of training.

Another example of non-pharmacological intervention is pulmonary rehabilitation. Pulmonary rehabilitation is a comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies that include, but are not limited to, exercise training, education, and behaviour change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviours (44). The benefits to COPD patients from pulmonary rehabilitation are considerable and rehabilitation has been shown to be the most effective therapeutic strategy to improve shortness of breath, health status and exercise tolerance (45). Oxygen therapy can also be an option for patients with hypoxemia. In patients with chronic respiratory failure with severe resting hypoxemia, the long-term administration of oxygen (>15 hour per day) has shown to increase survival (46). However, long-term oxygen therapy does not lengthen time to death or first hospitalisation or provide sustained benefit for any of the measured outcomes in patients with stable COPD and resting or exercise-induced moderate arterial oxygen desaturation (47). Several surgical interventional therapies also exist for COPD, including lung volume reduction surgery (LVRS), bullectomy and lung transplantation. In carefully selected patients, LVRS increases the elastic recoil pressure of the lung and thus improves expiratory flow rates and reduces exacerbations (48, 49). During a bullectomy, large bullae that do not contribute to gas exchange are removed. In selected patients with relatively preserved underlying lung, bullectomy is associated with decreased dyspnoea, improved lung function and exercise tolerance (50). In selected patients with severe COPD, lung transplantation has been shown to improve health status and functional capacity but not prolong survival (50-52). Recently, less invasive bronchoscopic interventions to reduce hyperinflation in severe emphysema have been investigated in the treatment of COPD patients. Prospective studies have shown that the use of bronchial stents is not effective (53). Endobronchial valve and lung coil therapies have shown statistically significant improvements in FEV1 and 6-minute walk distance (54-57). However, the magnitude of these improvements was not

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clinically meaningful in one study (54). Additional data are needed to define the optimal patient population to receive the specific bronchoscope lung volume technique and to compare the long-term durability of improvements in functional or physiological performance to lung volume reduction surgery relative to side-effects (57).

In patients with severe asthma (GINA report step 5) who’s disease remains uncontrolled, bronchial thermoplasty is a possible treatment option. Bronchial thermoplasty involves treatment of the airways during three separate bronchoscopies with a localised radio frequency pulse (58). The treatment is associated with a large placebo effect (58). Bronchial thermoplastic treatment should be performed in adults with severe asthma only in the context of an independent Institutional Review Board-approved systematic registry or a clinical study so that further evidence about effectiveness and safety of the procedure can be accumulated (59).

Patient education is also a non-pharmacological treatment for patients with obstructive lung diseases that has great clinical impact. This issue will be discussed below.

Non-pharmacological treatment: patient education

Education is important for patients with chronic obstructive lung diseases, including asthma and COPD. Guidelines from the GINA and GOLD state that education can help to improve skills, ability to cope with illness and health status and that patient education should be an integral part of all health care professionals’ training and patient care and is relevant to patients of all ages. Educational interventions and action plans can be useful in smoking cessation and improve responses to acute exacerbations (60-62). Smoking cessation has the greatest capacity to influence the natural history of COPD. If effective resources and time are dedicated to smoking cessation, long-term quit success rates of up to 25% can be achieved (63). To effectively provide educational skills and self-management plans, health care providers must focus on shared decision making and partnership with the patient, as this can eventually lead to behavioural changes.

Nurses increasingly have responsibility for the management of patients with chronic diseases, including asthma and COPD. Often as part of disease management, nurses provide educational interventions to support patient self-management. Treatment of chronic obstructive lung diseases is complex and multiple care-givers need to work together closely. In primary care, collaboration between physicians and nurses has shown to have a positive impact on patient satisfaction (64). Importantly, higher satisfaction with care in turn is associated with improved adherence to medication regimes (65).

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At the beginning of this century, the time this thesis was started, recommendations for educational interventions were less clear and the role of collaboration in care provided between nurses and physicians was evolving. Hence, there was a lack of data on the effectiveness of educational care provided by nurses for patients with obstructive lung diseases in an outpatient clinic. Systematic reviews showed that education improved health outcomes in asthma (66, 67), whereas for COPD this was less clear (68-70). However, the reviewed studies suffer from various methodological problems: there was no homogeneity in the interventions and study populations and follow-up time showed large variation. Moreover, the instruments that were used to assess patient relevant outcomes were not validated nor was it always clear how the instruments were constructed.

Clinimetrics

Educational care can be evaluated by outcomes in terms of exacerbation frequency, inhalation technique, patient satisfaction, self-management and health-related quality of life (HRQoL). For the assessment of HRQoL, there is a wide range of generic and disease-specific questionnaires available. Examples of clinimetrically sound instruments to measure QoL in patients suffering from asthma or COPD are the SF-36 which measures general HRQoL (71, 72)and the St. George’s respiratory questionnaire (SGRQ) which assesses disease specific HRQoL (73, 74).

For other outcomes such as adequacy of inhalations technique and satisfaction with care validated instruments in the field of chronic pulmonary diseases are less common. For example, little is known about the reliability in the assessment of inhalation technique. Only two studies investigated the inter- and intra-observer consistency in the evaluation of inhalation technique (75, 76)and both studies conclude that to achieve a reliable evaluation of inhalation technique, substantial training and practice is required. Researchers involved in inhalation technique evaluation should be trained to achieve consistency and to improve accuracy of research results, at least two evaluators should evaluate inhalation technique or take other measures to show and report reliability (76). Despite the growing awareness to assess patient’s satisfaction with provide care, hardly any clinimetric research has so far been done in patients with asthma and COPD. A feasible, reliable and valid questionnaire to measure patient’s satisfaction with pulmonary care is therefore urgently needed.

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Aim and outline of this Thesis

The aim of the present thesis is to capture different phenotypes of patients with obstructive lung disease, and to investigate non-pharmacological treatment outcomes.

First, we will focus on the identification of phenotypes of obstructive lung diseases in a regular outpatient clinic population, using the statistical approach of cluster analysis (Chapter 2). In the next two chapters we pay clinimetric attention to

important outcome indicators of educational care. In Chapter 3 we investigate the

feasibility, reliability, and validity of a new developed questionnaire that investigates the satisfaction with care received at a pulmonary outpatient clinic. In Chapter 4

we determined the reliability of video-taped inhalation technique assessments for frequently used devices. Chapter 5 presents a randomised clinic trial investigating the

effectiveness of an additional information-based nursing care program for asthma and COPD in a pulmonary outpatient clinic. Finally, we investigate determinants that are associated with poor medication inhalation technique (chapter 6). The

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29. Kunz LI, Lapperre TS, Snoeck-Stroband JB, et al. Smoking status and anti-inflammatory macrophages in bronchoalveolar lavage and induced sputum in COPD. Respir Res. 2011;12:34.

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31. Nannini LJ, Cates CJ, Lasserson TJ, et al. Combined corticosteroid and long-acting beta-agonist in one inhaler versus inhaled steroids for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2007(4):CD006826.

32. Nannini LJ, Poole P, Milan SJ, et al. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013(8):CD006826.

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34. Vestbo J, Anderson JA, Brook RD, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet. 2016;387(10030):1817-26.

35. Wongsurakiat P, Maranetra KN, Wasi C, et al. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest. 2004;125(6):2011-20. 36. Poole PJ, Chacko E, Wood-Baker RW, et al. Influenza vaccine for patients with chronic obstructive

pulmonary disease. Cochrane Database Syst Rev. 2006(1):CD002733.

37. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged >/=65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63(37):822-5.

38. Sheikh A, Alves B, Dhami S. Pneumococcal vaccine for asthma. Cochrane Database Syst Rev. 2002(1):CD002165.

39. Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J. 2002;19(2):246-51.

40. Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011;105(6):930-8.

41. Souza ML, Meneghini AC, Ferraz E, et al. Knowledge of and technique for using inhalation devices among asthma patients and COPD patients. J Bras Pneumol. 2009;35(9):824-31.

42. Sanchis J, Gich I, Pedersen S, et al. Systematic Review of Errors in Inhaler Use: Has Patient Technique Improved Over Time? Chest. 2016;150(2):394-406.

43. Laube BL, Janssens HM, de Jongh FH, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011;37(6):1308-31.

44. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013;188(8):e13-64.

45. McCarthy B, Casey D, Devane D, et al. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015(2):CD003793.

46. Cranston JM, Crockett AJ, Moss JR, et al. Domiciliary oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005(4):CD001744.

47. Term Oxygen Treatment Trial Research G, Albert RK, Au DH, et al. A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation. N Engl J Med. 2016;375(17):1617-27.

48. Fessler HE, Permutt S. Lung volume reduction surgery and airflow limitation. Am J Respir Crit Care Med. 1998;157(3 Pt 1):715-22.

49. Washko GR, Fan VS, Ramsey SD, et al. The effect of lung volume reduction surgery on chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;177(2):164-9.

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50. Marchetti N, Criner GJ. Surgical Approaches to Treating Emphysema: Lung Volume Reduction Surgery, Bullectomy, and Lung Transplantation. Semin Respir Crit Care Med. 2015;36(4):592-608.

51. Stavem K, Bjortuft O, Borgan O, et al. Lung transplantation in patients with chronic obstructive pulmonary disease in a national cohort is without obvious survival benefit. J Heart Lung Transplant. 2006;25(1):75-84.

52. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant. 2012;31(10):1073-86.

53. Shah PL, Slebos DJ, Cardoso PF, et al. Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial. Lancet. 2011;378(9795):997-1005.

54. Sciurba FC, Ernst A, Herth FJ, et al. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010;363(13):1233-44.

55. Klooster K, ten Hacken NH, Hartman JE, et al. Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation. N Engl J Med. 2015;373(24):2325-35.

56. Deslee G, Mal H, Dutau H, et al. Lung Volume Reduction Coil Treatment vs Usual Care in Patients With Severe Emphysema: The REVOLENS Randomized Clinical Trial. JAMA. 2016;315(2):175-84.

57. Sciurba FC, Criner GJ, Strange C, et al. Effect of Endobronchial Coils vs Usual Care on Exercise Tolerance in Patients With Severe Emphysema: The RENEW Randomized Clinical Trial. JAMA. 2016;315(20):2178-89.

58. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181(2):116-24.

59. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-73.

60. Howcroft M, Walters EH, Wood-Baker R, et al. Action plans with brief patient education for exacerbations in chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016;12:CD005074.

61. Lenferink A, Brusse-Keizer M, van der Valk PD, et al. Self-management interventions including action plans for exacerbations versus usual care in patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2017;8:CD011682.

62. Rice VH, Heath L, Livingstone-Banks J, et al. Nursing interventions for smoking cessation. Cochrane Database Syst Rev. 2017;12:CD001188.

63. van Eerd EA, van der Meer RM, van Schayck OC, et al. Smoking cessation for people with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016(8):CD010744.

64. Matthys E, Remmen R, Van Bogaert P. An overview of systematic reviews on the collaboration between physicians and nurses and the impact on patient outcomes: what can we learn in primary care? BMC Fam Pract. 2017;18(1):110.

65. Fortuna RJ, Nagel AK, Rocco TA, et al. Patient Experience With Care and Its Association With Adherence to Hypertension Medications. Am J Hypertens. 2018;31(3):340-5.

66. Gibson PG, Powell H, Coughlan J, et al. Self-management education and regular practitioner review for adults with asthma. Cochrane Database Syst Rev. 2003(1):CD001117.

67. Powell H, Gibson PG. Options for self-management education for adults with asthma. Cochrane Database Syst Rev. 2003(1):CD004107.

68. Monninkhof E, van der Valk P, van der Palen J, et al. Self-management education for patients with chronic obstructive pulmonary disease: a systematic review. Thorax. 2003;58(5):394-8.

69. Gadoury MA, Schwartzman K, Rouleau M, et al. Self-management reduces both short- and long-term hospitalisation in COPD. Eur Respir J. 2005;26(5):853-7.

70. Taylor SJ, Candy B, Bryar RM, et al. Effectiveness of innovations in nurse led chronic disease management for patients with chronic obstructive pulmonary disease: systematic review of evidence. BMJ. 2005;331(7515):485.

71. Ware JE SK, Kosinski M, Gandek B. SF-36 health survey manual and interpretation guide. Boston, MA: New England Medical Center: The Health Institute; 1993.

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72. Aaronson NK, Muller M, Cohen PD, et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol. 1998;51(11):1055-68.

73. Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med. 1991;85 Suppl B:25-31; discussion 3-7.

74. Jones PW, Quirk FH, Baveystock CM, et al. A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145(6):1321-7. 75. O’Connell MB, Hewitt JM, Lackner TE. Consistency of evaluators assessing inhaler technique. Ann

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Chapter 2

J Asthma. 2016 Dec;53(10):1026-32.

G Rootmensen, A van Keimpema, A Zwinderman, P Sterk

Clinical phenotypes of

obstructive airway diseases

in an outpatient population

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Abstract

Background and Objectives: Historically, obstructive airway diseases such as asthma

and COPD are classified as different diseases. Although the definitions are clearly described, classification of patients into these traditional, clinical disease entity can be difficult. Recent evidence that there are complex, overlapping phenotypes of obstructive lung disease. Our aim was to capture clinical phenotypes of obstructive diseases through the use of cluster analysis in a representative patient population at a common Dutch pulmonary outpatient clinic. Clinical physiological and cellular/ molecular markers were used in the analysis.

Methods: In order to carry out the cluster analysis, an imputed dataset was created

from a random sample of 191 adult patients chosen from a pulmonary outpatient clinic. The selection criteria from the sample included patients with a doctor’s diagnosis for asthma or COPD. Detailed assessment of patient pulmonary function, blood eosinophil counts, allergic sensitisation and smoking history was collected.

Results: We observed four distinct clusters with different clinical characteristics of

obstructive lung diseases. Cluster 1: patients with a history of extensive cigarette smoking, airway obstruction without signs of emphysema; cluster 2: patients with features of the emphysematous type of COPD; cluster 3: patients with characteristics of allergic asthma; cluster 4: patients with features suggesting an overlap syndrome of atopic asthma and COPD.

Conclusion: Four phenotypes of obstructive lung disease were identified amongst

patients clinically labelled as asthma or COPD. These findings emphasise the concept that there are different phenotypes of obstructive lung diseases, including overlapping and complementary disease entities. These phenotypes of chronic airways disease can serve to tailor disease management.

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Introduction

Historically, obstructive pulmonary diseases have been classified into distinct diseases such as asthma and COPD, including disorders such as chronic bronchitis and emphysema. These different clinical entities appear to be heterogeneous and are generally characterised by a number of features including: specific symptom complexes, exposure to certain risk factors, variable patterns of airway obstruction, airway hyper-responsiveness, and different types of airway inflammation (1-5). The current global consensus statements are still using specific criteria to establish the clinical diagnosis. For example, the diagnosis of COPD requires the ratio of post bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) being below 0.7 (6). Recently, the use of an age-specific, sex-specific, height-specific and ethnic-height-specific lower limit of normal (LLN) in the diagnostics of airway obstruction in COPD is discussed (7). In asthma the diagnosis is based on reversible airway obstruction that varies spontaneously or improves after treatment (8). Even though these definitions are clear, they are not mutually exclusive.

There are many patients that have clinical features for both diagnoses asthma and COPD and as such, classification of day-to-day patients into specific clinical disease entities asthma or COPD has shown to be difficult (9-11). For instance, reversible airway obstruction is a physiological characteristic and clinical feature of asthma, but may also be present in a substantial proportion of patients with COPD (12-14). In addition, a subgroup of patients with longstanding asthma shows an accelerated loss of lung function and has impaired post bronchodilator spirometry (15), thereby meeting criteria for COPD (16-18). Recently, the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) issued a joined document (available at www.ginasthma.org/local/uploads/files/ACOS_2015. pdf or www.goldcopd.org/uploads/users/files/GOLD_ACOS_2015.pdf) that describes the asthma COPD overlap syndrome (ACOS) as a clinical disease entity and suggests that physicians should compile the features for asthma and for COPD that best describe the patient and compare the number of features in favour of each diagnosis.

If similar features of asthma and COPD are present, the diagnosis ACOS can be considered. Alternatively, it has recently been advocated to put emphasis on the treatable phenotypes rather than the traditional diagnosis in the management of patients with chronic airways disease (19). These patients may or may not be classified as the overlap syndrome between COPD and asthma (9), which not only appears to be characterised by distinguishable clinical characteristics but also by

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separate genetic variants (20).

This is problematic because, notably, the subgroups of patients not meeting the classic criteria for the traditional diagnosis of asthma or COPD are usually not included in randomised controlled medication trials. This could potentially result in an inadequate basis of evidence for treatment benefits (5). Therefore, the recognition of different phenotypes within obstructive lung diseases is not only important for understanding the underlying disease processes, but is also clinically relevant due to potentially different responses to therapeutic interventions (9, 21, 22).

In order to discover previously unrecognised phenotypes of obstructive lung diseases several models have been developed. The traditional approach has been to present the overlap of a priori defined phenotypes as a Venn diagram of clinical presentations of asthma and COPD (23). However, this results in at least 15 phenotypes, whose pathogenesis or responses to treatment have not been clearly defined (24).

Cluster analysis is a validated approach to describe different patterns of patient groups based on clinical, physiological and biological features of obstructive lung diseases. Cluster analysis is a collection of methods without a priori hypothesis that can be used for defining subgroups of individuals based on measured characteristics. This approach has previously been used in patient populations with asthma (25-27), COPD (27-32) and combined diagnosis asthma and COPD (3, 5, 33-36).

A vast majority of cluster analysis studies have been performed using carefully prepared patient selections with strict inclusion and exclusion criteria, some were performed on population samples (1) or unselected patient populations (36). However, exclusion of specific patients decreases the reliability of achieving a representative classification of different phenotypes as encountered in regular clinical practice.

The aim of the present study was to identify the clinical phenotypes of obstructive airway diseases in a common pulmonary outpatient clinical setting by cluster analysis. For this study, patients receiving treatment for an obstructive lung disease like asthma or COPD at a regular Dutch pulmonary outpatient clinic were randomly selected. Any formal selection criteria were intentionally left out, apart from being diagnosed by a pulmonary physician as having asthma or COPD. We used clinical, physiological and cellular/molecular markers as entry into the cluster analysis.

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Methods

Patients

Patients were recruited from a trial investigating the effects of additive nursing care in a pulmonary outpatient clinic in Amsterdam, The Netherlands (37). The outpatient clinic is representative for a 2nd line care centre serving GP’s. Patients were selected randomly from the outpatient clinic and were eligible to participate in this trial if they 1) were over 18 years 2) were diagnosed as having asthma (8) or COPD (6) by pulmonary physicians, 3) understood Dutch sufficiently to answer the questionnaires and 4) never had consulted a pulmonary nurse. The study was approved by the Medical Ethics Study of the Academic Medical Centre in Amsterdam, The Netherlands and patients gave written informed consent.

Design and measurements

The study had a cross-sectional design including two visits per patient in six months. The following spirometry data were collected at the first visit of the study: maximal vital capacity (VCmax), forced expiratory volume in 1 second (FEV1), ratio FEV1/VCmax. Reversibility of airway obstruction was measured ten minutes after administration of 400μg inhaled salbutamol per metered dose inhaler (MDI) with spacer and expressed as change in FEV1 as percentage of predictive value.

The diffusing capacity for carbon monoxide per litre alveolar volume and adjusted for haemoglobin (DLCOc/VA) was measured using the single breath holding method. During the assessment of lung function, length and weight were collected. Spirometry data were collected during regular outpatient clinic visits and could be performed with continuation of prescribed inhalation medication. The total blood eosinophil counts and allergic sensitisation (specific IgE) to aero-allergens (Phadiatop, a combination of most common aero-allergens) were measured in the blood.

Statistical methods

SPSS (version 18.0) was used for data analysis. Cluster analysis was carried out on the data set with the subjects defined as described using the following eight variables: 1) Body Mass Index (BMI); 2) post-bronchodilator FEV1 expressed as a percentage of the predicted value; 3) post-bronchodilator FEV1/VCmax ratio expressed as a percentage; 4) post-bronchodilator change in FEV1, expressed as percentage from predictive value; 5) diffusing capacity (DLCOc/VA) expressed as a percentage of the predicted value; 6) total counts of peripheral blood eosinophils; 7) cumulative cigarette consumption (in pack-years); and 8) sensitisation by Phadiatop.

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These variables cover the available information about the various aspects of obstructive pulmonary disease in the present outpatient setting, being representative of the common parameters that are used in day-to-day outpatient care. Moreover, this selection of variables was intended to match previous studies (3, 5). All variables were equally weighted and by logarithmic transformation of total eosinophils we ensured that extreme values did not form clusters. In addition to the eight primary variables, all clinical and demographic characteristics of the subjects in the clusters are also presented in a separate table. The method of scoring inhalation technique and questionnaires assessing disease-knowledge, self-management and validated inhalation technique score have previously been described (37, 38).

Missing values were considered to be at random (39, 40). Multiple imputation method by Rubin & Schenker (41) was used for the generation of missing data replacements based on values drawn from the distribution posited by the prediction model, taking into account the relationships between the incomplete variables and all other variables (39). Five newly imputed datasets were created and cluster analysis (K-means) was performed on the six datasets. Analysis of all six datasets showed similar cluster results. One generated dataset was randomly chosen for description of the variables of the clusters (40). The number of clusters was based on statistic analysis using maximised GAP statistics and minimised average silhouette width. Moreover, a cluster needed to include minimally of 10 subjects. A dendrogram or tree diagram is presented to show progressive divisions or merging of the clustering process.

Results

The mean age of patients in the trial was 61 years (SD 15). The ratio between female/ male participants was 83/109 (43/57%). In total 111 patients (58%) were diagnosed by their treating physician as having COPD and 80 patients (42%) as asthma. Of the approached patients (n=210), nineteen persons declined to participate in the trial.

The five imputed baseline datasets of the 191 patients showed similar characteristics to the original dataset for the determinants that were used for the cluster analysis (Table 1). Imputed dataset number 3 was randomly chosen for description of the clusters, data of other imputed datasets can be found in Table 1 in the online supporting information. The dendrogram for the cluster analysis is presented in Figure 1. The analysis identified four distinct clusters (Table 2).

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Cluster 1 patients can be described as COPD patients without signs of emphysema.

Patients in this cluster have a history of extensive cigarette smoking, mild airway obstruction and preserved diffusion capacity. Compared to the second cluster (COPD patients with features of emphysema), this group of patients has a higher BMI. The first cluster shows limited signs of atopic sensitisation and low serum eosinophil counts.

Cluster 2 groups patients with features of the emphysematous type of COPD. Patients

in this cluster exhibit decreased diffusion capacity, severe airway obstruction and a moderate history of smoking. Additional characteristics are low BMI and limited atopy with low percentage of positive Phadiatop and low serum eosinophil counts.

Cluster 3 comprises patients with characteristics of allergic asthma. These patients

do not have a history of severe smoking, show limited or absent airway obstruction and the majority of patients are atopic with a positive Phadiatop and increased counts of blood eosinophils. Compared to the other clusters, patients in this cluster show higher reversibility in airway obstruction after salbutamol.

Cluster 4 groups patients with features suggesting an overlap syndrome of atopic

asthma and COPD. This cluster exhibits fixed airway obstruction together with high levels of blood eosinophils and a majority with atopy.

Additional demographical and clinical characteristics of the four clusters are presented in table 3.

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Discussion

The aim of our study was to identify different phenotypes of obstructive lung diseases in a pulmonary outpatient clinic by cluster analysis. We found four distinct patient groups with different clinical characteristics of obstructive lung diseases. Notably, by using unbiased data analysis three clusters followed typical clinical diagnoses such as atopic asthma and non-atopic COPD. On the other hand, cluster 4 represented an explicit overlap population between traditional diagnoses of asthma and COPD, thereby supporting the concept of overlap between the different types of obstructive lung disease that could include ACOS (9, 11, 20). It needs to be emphasised that most of our patients would have been excluded for medication trials for asthma or COPD. Therefore, it seems mandatory to expand clinical trials into more realistic phenotypes of patients, including those that do not meet the classical diagnostic criteria.

Multidimensional assessment of asthma and COPD is increasingly recognised as an effective approach to discover clinically relevant phenotypes that may differ in both natural course of disease and response to therapies (42, 43). Cluster analysis has previously been used as a means of exploration for different phenotypes of obstructive lung diseases (3, 5, 27, 29-32, 35, 36). The four phenotypes that were identified in this study endorse and extend phenotypes that were found in previous studies. Each of the present 4 subtypes, mild COPD (cluster 1) (29, 31, 35), COPD with mainly characteristics of emphysema (cluster 2) (3, 5, 29, 31, 35), allergic asthmatic (cluster 3) (5), and finally the group of overlap syndrome asthma/COPD (cluster 4) (5, 36) were described in previous studies, but thus far these have not been identified in a single comprehensive analysis covering a clinical population of asthma as well as COPD. Therefore, the present study validates previous fragmented evidence of partly overlapping phenotypes between asthma and COPD. These findings support clinical description of the asthma COPD overlap syndrome (ACOS) (18) or probably better, a full phenotypic characterisation to promote tailored disease management (19). To our knowledge, this is the second study that was performed in an unselected, representative group of patients that were treated for an obstructive lung disease in a pulmonary outpatient clinic. Weatherall et al. performed a cluster analysis on a sample of patients with signs of obstructive lung disease that were selected from a random population in New Zealand ( 5). Although their selection of subjects was not a clinical one, the resulting clusters showed similarities. Additionally, in recent research, Ghebre et al. performed a cluster analysis on patients with severe asthma and mild to moderate COPD from a single centre. Although the selection of patient characteristics used in this cluster analysis was more focused on inflammatory markers in sputum, an asthma/COPD overlap group was also revealed in this trial (36).

Obstructive lung diseases at an outpatient clinic: Phenotypes and non-pharmacological treatment outcomes - Thesis

UvA-DARE (Digital Academic Repository)

Obstructive lung diseases at an outpatient clinic

Phenotypes and non-pharmacological treatment outcomes

Rootmensen, G.N.

Publication date

2020

Document Version

Final published version

License

Other

Link to publication

Citation for published version (APA):

Rootmensen, G. N. (2020). Obstructive lung diseases at an outpatient clinic: Phenotypes and

non-pharmacological treatment outcomes.

Obstructive lung diseases at an outpatient clinic:

phenotypes and non-pharmacological

treatment outcomes

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Obstructive lung diseases at an outpatient clinic:

phenotypes and non-pharmacological treatment outcomes

Geert Nico Rootmensen

Contents

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Chapter 1

General introduction and

Obstructive Lung Diseases: Asthma and Chronic Obstructive

Pulmonary Disease

Phenotypes of Obstructive Lung Diseases

Treatment of Obstructive Lung Diseases

Clinimetrics

Aim and outline of this Thesis

References

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Chapter 2

Clinical phenotypes of

obstructive airway diseases

in an outpatient population

Abstract

Introduction

Methods

Patients

Design and measurements

Statistical methods

Results

Discussion