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<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Med.</journal-id>
<journal-title>Frontiers in Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Med.</abbrev-journal-title>
<issn pub-type="epub">2296-858X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fmed.2024.1375457</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Medicine</subject>
<subj-group>
<subject>Mini Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Chronic obstructive pulmonary disease (COPD) and COPD-like phenotypes</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name><surname>Fortis</surname> <given-names>Spyridon</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<xref ref-type="corresp" rid="c001"><sup>&#x002A;</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/1144294/overview"/>
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</contrib>
<contrib contrib-type="author">
<name><surname>Georgopoulos</surname> <given-names>Dimitris</given-names></name>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
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<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Tzanakis</surname> <given-names>Nikolaos</given-names></name>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
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</contrib>
<contrib contrib-type="author">
<name><surname>Sciurba</surname> <given-names>Frank</given-names></name>
<xref ref-type="aff" rid="aff4"><sup>4</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Zabner</surname> <given-names>Joseph</given-names></name>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/39258/overview"/>
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<contrib contrib-type="author">
<name><surname>Comellas</surname> <given-names>Alejandro P.</given-names></name>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
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<aff id="aff1"><sup>1</sup><institution>Center for Access and Delivery Research and Evaluation, Iowa City VA Health Care System</institution>, <addr-line>Iowa City, IA</addr-line>, <country>United States</country></aff>
<aff id="aff2"><sup>2</sup><institution>Division of Pulmonary, Critical Care and Occupational Medicine, Department of Internal Medicine, University of Iowa</institution>, <addr-line>Iowa City, IA</addr-line>, <country>United States</country></aff>
<aff id="aff3"><sup>3</sup><institution>Medical School, University of Crete</institution>, <addr-line>Heraklion</addr-line>, <country>Greece</country></aff>
<aff id="aff4"><sup>4</sup><institution>Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh</institution>, <addr-line>Pittsburgh, PA</addr-line>, <country>United States</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Roberto Carbone, University of Genoa, Italy</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Valerie G. Press, The University of Chicago, United States</p></fn>
<corresp id="c001">&#x002A;Correspondence: Spyridon Fortis, <email>spyridon-fortis@uiowa.edu</email></corresp>
</author-notes>
<pub-date pub-type="epub">
<day>09</day>
<month>04</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>11</volume>
<elocation-id>1375457</elocation-id>
<history>
<date date-type="received">
<day>23</day>
<month>01</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>20</day>
<month>03</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x00A9; 2024 Fortis, Georgopoulos, Tzanakis, Sciurba, Zabner and Comellas.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Fortis, Georgopoulos, Tzanakis, Sciurba, Zabner and Comellas</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license>
</permissions>
<abstract>
<p>Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease. Historically, two COPD phenotypes have been described: chronic bronchitis and emphysema. Although these phenotypes may provide additional characterization of the pathophysiology of the disease, they are not extensive enough to reflect the heterogeneity of COPD and do not provide granular categorization that indicates specific treatment, perhaps with the exception of adding inhaled glucocorticoids (ICS) in patients with chronic bronchitis. In this review, we describe COPD phenotypes that provide prognostication and/or indicate specific treatment. We also describe COPD-like phenotypes that do not necessarily meet the current diagnostic criteria for COPD but provide additional prognostication and may be the targets for future clinical trials.</p>
</abstract>
<kwd-group>
<kwd>chronic obstructive pulmonary disease</kwd>
<kwd>phenotypes text word count: 2</kwd>
<kwd>chronic hypercapnic respiratory failure</kwd>
<kwd>chronic hypoxemic respiratory failure</kwd>
<kwd>preserved ratio impaired spirometry (PRISm)</kwd>
<kwd>hyperinflation</kwd>
<kwd>preserved spirometry at risk for COPD</kwd>
<kwd>frequent respiratory exacerbations</kwd>
</kwd-group>
<counts>
<fig-count count="1"/>
<table-count count="1"/>
<equation-count count="0"/>
<ref-count count="79"/>
<page-count count="8"/>
<word-count count="6084"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Pulmonary Medicine</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="S1" sec-type="intro">
<title>Introduction</title>
<p>Chronic obstructive pulmonary disease (COPD) is defined as persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities usually caused by noxious particles or gases and influenced by host factors (<xref ref-type="bibr" rid="B1">1</xref>). COPD diagnosis requires not only a consistent history but also the presence of airflow limitation via spirometry. Historically, two phenotypes have been described to further characterize the disease: <italic>chronic bronchitis</italic>, which is associated with airway inflammation with the main characteristic being chronic productive cough, and <italic>emphysema</italic>, which is associated with alveolar destruction and presents with dyspnea. Although these phenotypes provide some additional characterization of the pathophysiology of the disease, they are not extensive enough to reflect the heterogeneity of COPD and do not provide granular categorization that indicates specific treatment, perhaps with the exception of adding inhaled glucocorticoids (ICS) in patients with chronic bronchitis (<xref ref-type="bibr" rid="B2">2</xref>). Moreover, the current definition of COPD does not include individuals with high respiratory burden, e.g., high mortality and frequent respiratory hospitalizations, that do not have airflow limitation (<xref ref-type="bibr" rid="B3">3</xref>&#x2013;<xref ref-type="bibr" rid="B5">5</xref>). The first objective of this review is to describe clinically relevant COPD phenotypes that provide prognostication and/or indicate specific treatment (<xref ref-type="fig" rid="F1">Figure 1</xref>). The second objective is to describe COPD-like phenotypes that do not necessary meet the current diagnostic criteria for COPD but provide additional prognostication and may indicate response to certain treatments that can be tested in future clinical trials. <xref ref-type="table" rid="T1">Table 1</xref> provides a summary of all phenotypes.</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption><p>Clinically relevant COPD phenotypes and corresponding treatments.</p></caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fmed-11-1375457-g001.tif"/>
</fig>
<table-wrap position="float" id="T1">
<label>TABLE 1</label>
<caption><p>Summary of chronic obstructive pulmonary disease (COPD) and COPD-like phenotypes.</p></caption>
<table cellspacing="5" cellpadding="5" frame="box" rules="all">
<thead>
<tr>
<td valign="top" align="left" style="color:#ffffff;background-color: #7f8080;">Phenotypes</td>
<td valign="top" align="left" style="color:#ffffff;background-color: #7f8080;"></td>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">Asthma-COPD overlap and COPD with eosinophilia</td>
<td valign="top" align="left">High eosinophils in patients with COPD indicate obstructive lung disease that responds to ICS, and high eosinophils and BDR may indicate disease that responds to biological therapy.</td>
</tr>
<tr>
<td valign="top" align="left">COPD with static hyperinflation</td>
<td valign="top" align="left">Lung volume reduction in selected patients with severe lung function impairment and static hyperinflation is associated with improvement in lung function, exercise capacity, and quality of life.</td>
</tr>
<tr>
<td valign="top" align="left">COPD with chronic hypoxemic respiratory failure</td>
<td valign="top" align="left">Oxygen supplementation in patients with COPD and resting chronic hypoxemic respiratory failure improves survival but is not beneficial in those with isolated exertional or nocturnal hypoxemia.</td>
</tr>
<tr>
<td valign="top" align="left">COPD with chronic hypercapnic respiratory failure</td>
<td valign="top" align="left">Home nocturnal non-invasive ventilation in patients with COPD and chronic hypercapnic respiratory failure improves survival and reduces hospitalizations.</td>
</tr>
<tr>
<td valign="top" align="left">COPD with frequent respiratory exacerbations</td>
<td valign="top" align="left">Frequent respiratory exacerbations may indicate escalation of treatment (ICS, azithromycin, roflumilast, home NIV) and further investigation is required to identify other conditions, e.g., antibody deficiency syndrome, that may benefit from additional treatment.</td>
</tr>
<tr>
<td valign="top" align="left">Preserved spirometry at risk for COPD</td>
<td valign="top" align="left">Individuals with normal spirometry and history of smoking who have chronic bronchitis or respiratory exacerbations have increased respiratory-related hospitalizations and mortality. Further research is needed to assess preventive treatment for individuals with normal spirometry but who are at risk of progressing to COPD.</td>
</tr>
<tr>
<td valign="top" align="left">Preserved ratio impaired spirometry (PRISm)</td>
<td valign="top" align="left">PRISm is a volatile spirometric pattern associated with respiratory symptoms and mortality. Further research is needed to confirm whether individuals with PRISm benefit from existing treatment for COPD.</td>
</tr>
</tbody>
</table></table-wrap>
</sec>
<sec id="S2">
<title>Asthma-COPD overlap and COPD with eosinophilia</title>
<p>Asthma-COPD overlap is a relatively new term that describes the coexistence of asthma and COPD (<xref ref-type="bibr" rid="B6">6</xref>). Definitions have been proposed by scientific groups including the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the Global Initiative for Asthma (GINA) but none offer prognostication and do not indicate specific treatment (<xref ref-type="bibr" rid="B7">7</xref>). Because bronchodilator responsiveness (BDR) is one of several criteria to confirm lung function variability, (<xref ref-type="bibr" rid="B8">8</xref>) BDR presence is often and erroneously considered equivalent to asthma diagnosis. Although BDR is more common and greater in patients with asthma than those with COPD, BDR cannot distinguish asthma and COPD (<xref ref-type="bibr" rid="B9">9</xref>&#x2013;<xref ref-type="bibr" rid="B11">11</xref>). Further, the association of BDR with clinical outcomes in patients with COPD has been extensively studied with conflicting findings (<xref ref-type="bibr" rid="B12">12</xref>&#x2013;<xref ref-type="bibr" rid="B14">14</xref>). Early studies showed that BDR cannot predict response to treatment (<xref ref-type="bibr" rid="B12">12</xref>&#x2013;<xref ref-type="bibr" rid="B14">14</xref>). The only outcome which is consistently associated with BDR is FEV<sub>1</sub> decline over time (<xref ref-type="bibr" rid="B15">15</xref>&#x2013;<xref ref-type="bibr" rid="B17">17</xref>). The inconsistent findings regarding the association of BDR and clinical outcomes may be related to various BDR definitions and protocols. In COPD, an increase in both FEV<sub>1</sub> and FVC by 12% and 200 ml after bronchodilator administration was associated with a phenotype that is characterized by less emphysema but reduced mortality (<xref ref-type="bibr" rid="B15">15</xref>). BDR in FVC is typically associated with greater degree of emphysema (<xref ref-type="bibr" rid="B18">18</xref>, <xref ref-type="bibr" rid="B19">19</xref>) and functional small airway disease (<xref ref-type="bibr" rid="B20">20</xref>). A drawback of BDR is its instability over time (<xref ref-type="bibr" rid="B14">14</xref>, <xref ref-type="bibr" rid="B15">15</xref>). Nevertheless, the hallmark of asthma is lung variability, and it is not surprising that BDR is not stable over time. A recent study showed that consistent BDR in individuals with former or current smoking exposure is associated with prior asthma diagnosis, lung function decline, and functional small airway disease (<xref ref-type="bibr" rid="B20">20</xref>).</p>
<p>Eosinophils are strongly tied with Th2-mediated inflammation, historically considered the type of inflammation that occurs in asthma, as opposed to Th1-mediated inflammation, typically present in COPD (<xref ref-type="bibr" rid="B6">6</xref>). Increased sputum and blood eosinophil counts indicate response to ICS and patients with COPD who have blood eosinophil counts &#x2265; 300 cells/&#x03BC;L should consider adding ICS combined with bronchodilator treatment (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B1">1</xref>). Biologic agents that target interleukin-5, interleukin-5 receptor and interleukin-4/interleukin-13 receptor in patients with COPD and elevated blood eosinophil counts reduce exacerbations (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B21">21</xref>, <xref ref-type="bibr" rid="B22">22</xref>). A post-hoc analysis of two randomized placebo controlled trials in COPD determined that the anti-IL5 agent benralizumab had greater response in patients with BDR in FEV<sub>1</sub> (<xref ref-type="bibr" rid="B23">23</xref>). This is the first study showing that BDR can indicate response to a specific pharmacological agent.</p>
<disp-quote>
<p><italic>Summary: High eosinophils in patients with COPD indicate obstructive lung disease that responds to ICS and biologics, and BDR may indicate disease with greater response to biological therapy.</italic></p>
</disp-quote>
</sec>
<sec id="S3">
<title>COPD with static hyperinflation</title>
<p>Hyperinflation often occurs in COPD as the disease progresses and is well known to be associated with poor prognosis (<xref ref-type="bibr" rid="B24">24</xref>&#x2013;<xref ref-type="bibr" rid="B27">27</xref>). The landmark study by Casanova et al. (<xref ref-type="bibr" rid="B25">25</xref>) showed that hyperinflation, defined as decreased inspiratory capacity to total lung capacity (TLC) ratio, is associated with increased mortality. More recently, studies confirm those findings using other definitions of hyperinflation (<xref ref-type="bibr" rid="B26">26</xref>, <xref ref-type="bibr" rid="B27">27</xref>). Several definitions exist which refer to whether measurements of hyperinflation occur during rest (static) or exercise (dynamic) and the measurement themselves, e.g., functional residual capacity, residual volume (RV) (<xref ref-type="bibr" rid="B28">28</xref>).</p>
<p>Lung volume reduction surgery can alleviate static and dynamic hyperinflation and improve outcomes, including mortality (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B30">30</xref>). In one study, patients with upper-predominant emphysema, low post-rehabilitation exercise capacity who underwent lung volume reduction surgery had a long-term survival benefit (<xref ref-type="bibr" rid="B29">29</xref>). Nevertheless, lung volume reduction surgery is associated with high perioperative mortality, limiting the enthusiasm for the procedure (<xref ref-type="bibr" rid="B31">31</xref>). Recently, endobronchial valves placed bronchoscopically, a significantly less invasive procedure than lung resection, have been used as an alternative method to reduce hyperinflation. Endobronchial valves decrease the size of hyperinflated areas of the lung by allowing air to exit the hyperinflated areas but not to re-enter it. By reducing hyperinflation, endobronchial valves have been shown to improve lung function, exercise capacity, quality of life, and may reduce mortality (<xref ref-type="bibr" rid="B24">24</xref>, <xref ref-type="bibr" rid="B32">32</xref>, <xref ref-type="bibr" rid="B33">33</xref>). Patients with COPD should not only have severe lung function impairment (FEV1% predicted &#x003C; 45%) and static hyperinflation (TLC &#x003E; 100% and RV &#x003E; 175%) but also need to have significantly reduced exercise capacity (6-min walk distance &#x003C; 450 m or 1,476 feet) to benefit from endobronchial valves (<xref ref-type="bibr" rid="B34">34</xref>). Moreover, these patients should not have severe alveolar gas exchange impairment (PaO<sub>2</sub> &#x003C; 45 mmHg, and PaCO<sub>2</sub> &#x003E; 50 mmHg) and significantly impaired exercised capacity which can increase the periprocedural risk. Chronic bronchitis is one of the exclusion criteria as it can be associated with difficultly clearing airways of the treated areas and risk of respiratory infections. Insertion of endobronchial valves are associated with 25&#x2013;30% risk for pneumothorax and for that reason requires inpatient observation for 3 days (<xref ref-type="bibr" rid="B32">32</xref>).</p>
<disp-quote>
<p><italic>Summary: Lung volume reduction in selected patients with severe lung function impairment and static hyperinflation is associated with improvement in lung function, exercise capacity, and quality of life.</italic></p>
</disp-quote>
</sec>
<sec id="S4">
<title>COPD with chronic hypoxemic respiratory failure</title>
<p>In the advanced stages of COPD, hypoxemia, defined as oxygen saturation below 89%, may develop. Oxygen supplementation in patients with COPD and chronic hypoxemic respiratory failure at rest has shown remarkable long-term mortality benefit with more than 50% increase in survival (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B35">35</xref>, <xref ref-type="bibr" rid="B36">36</xref>). However, the benefit of oxygen supplementation in isolated hypoxemia on exertion (absence of hypoxemia at rest) is either minimal or absent (<xref ref-type="bibr" rid="B37">37</xref>&#x2013;<xref ref-type="bibr" rid="B39">39</xref>). Emtner et al. (<xref ref-type="bibr" rid="B38">38</xref>) showed that oxygen supplementation increased exercise capacity in patients undergoing exercise training. Patients who received oxygen supplementation while exercising were able to train 4 min longer than those who did not receive oxygen. Nonoyama et al. (<xref ref-type="bibr" rid="B37">37</xref>) showed that oxygen supplementation improved a 5-min walk test by just 15 steps relative to air supplementation (control) (<xref ref-type="bibr" rid="B37">37</xref>). A large meta-analysis showed that oxygen supplementation in patients with COPD and isolated exertional hypoxemia does not improve any clinical outcome (<xref ref-type="bibr" rid="B40">40</xref>). Supplemental oxygen in those with moderate hypoxemia is also not beneficial (<xref ref-type="bibr" rid="B39">39</xref>, <xref ref-type="bibr" rid="B40">40</xref>). Oxygen supplementation in those with isolated nocturnal hypoxemia has no benefit despite that these patients may be hypoxemic more than half of the duration of their sleep (<xref ref-type="bibr" rid="B41">41</xref>, <xref ref-type="bibr" rid="B42">42</xref>).</p>
<disp-quote>
<p><italic>Summary: Oxygen supplementation in patients with COPD and resting chronic hypoxemic respiratory failure improves survival but it is not beneficial in those with isolated exertional or nocturnal hypoxemia.</italic></p>
</disp-quote>
</sec>
<sec id="S5">
<title>COPD with chronic hypercapnic respiratory failure</title>
<p>Chronic hypercapnic respiratory failure is another consequence of COPD that occurs in advanced stages of the disease and is associated with increased mortality (<xref ref-type="bibr" rid="B43">43</xref>&#x2013;<xref ref-type="bibr" rid="B45">45</xref>). The pathophysiological mechanism of chronic hypercapnic respiratory failure is complex and not entirely understood but hypoventilation seems to play the primary role (<xref ref-type="bibr" rid="B46">46</xref>, <xref ref-type="bibr" rid="B47">47</xref>). During sleep, hypoventilation is more pronounced and nocturnal home non-invasive ventilation (NIV) has been used in these patients (<xref ref-type="bibr" rid="B48">48</xref>). Early studies of home nocturnal NIV in those patients showed no benefit (<xref ref-type="bibr" rid="B49">49</xref>, <xref ref-type="bibr" rid="B50">50</xref>) but recent randomized controlled trials (RCTs) showed improvement in clinical outcomes, including reduction in hospitalizations and mortality benefit (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B51">51</xref>, <xref ref-type="bibr" rid="B52">52</xref>). Recent meta-analyses found an improvement in mortality, hospitalizations, dyspnea, exercise capacity, and health-related quality of life relative to standard treatment (<xref ref-type="bibr" rid="B53">53</xref>, <xref ref-type="bibr" rid="B54">54</xref>). It seems that the benefit is related to a particular ventilator strategy, known as high intensity, that includes large inspiratory to expiratory airway pressure difference, high minute ventilation, and reducing baseline CO<sub>2</sub> levels by 25%, as well as with selection of patients with severe disease, those with FEV<sub>1</sub>% predicted &#x003C; 50% and PaCO<sub>2</sub> &#x003E; 52 mmHg (<xref ref-type="bibr" rid="B51">51</xref>, <xref ref-type="bibr" rid="B52">52</xref>, <xref ref-type="bibr" rid="B55">55</xref>). RCTs with favorable outcomes recruited patients with severe lung function impairment and hypercapnia who had a recent COPD-related hospitalization or chronic hypoxemic respiratory failure (<xref ref-type="bibr" rid="B51">51</xref>, <xref ref-type="bibr" rid="B52">52</xref>, <xref ref-type="bibr" rid="B56">56</xref>). A recent metanalysis showed that both higher baseline arterial CO<sub>2</sub> levels and greater magnitude of the CO<sub>2</sub> reduction from NIV are associated with greater improvement in clinical outcomes (<xref ref-type="bibr" rid="B53">53</xref>). Nevertheless, this may merely reflect that these patients are sicker and benefit more from treatment. Despite the significant benefits from home nocturnal NIV, it is underutilized among those with COPD-related hospitalizations, with less than 3% of those patients using bilevel positive airway pressure/home NIV (<xref ref-type="bibr" rid="B57">57</xref>, <xref ref-type="bibr" rid="B58">58</xref>).</p>
<disp-quote>
<p><italic>Summary: Home nocturnal non-invasive ventilation in patients with COPD and chronic hypercapnic respiratory failure improves survival and reduces hospitalizations.</italic></p>
</disp-quote>
</sec>
<sec id="S6">
<title>COPD with frequent respiratory exacerbations</title>
<p>This phenotype of COPD has attracted a lot of attention despite the small proportion of patients with this phenotype, due to fact that this group of patients consume the largest proportion of healthcare resources and have poor prognosis (<xref ref-type="bibr" rid="B59">59</xref>, <xref ref-type="bibr" rid="B60">60</xref>). Beeh et al. (<xref ref-type="bibr" rid="B59">59</xref>), in a sample of patients with moderate or severe COPD, showed that 14% of the patients accounted for 57% of the total COPD-related hospitalizations. In our previous work, among patients with COPD and mild-to-moderate lung function impairment, the top 5% in exacerbation frequency accounted for 34% of the total exacerbations in the cohort (<xref ref-type="bibr" rid="B60">60</xref>). Those with frequent exacerbations have increased mortality relative to those with no exacerbations (<xref ref-type="bibr" rid="B60">60</xref>). Although a formal definition for this phenotype does not exist, at least two moderate exacerbations or one hospitalization has been used as a cutoff to identify patients with COPD who require escalation of treatment according to GOLD guidelines (<xref ref-type="bibr" rid="B1">1</xref>). Patients with frequent exacerbations may benefit from addition of ICS on bronchodilator therapy, azithromycin, and roflumilast.</p>
<p>This phenotype is heterogenous and likely includes patients with chronic bronchitis, asthma-COPD overlap, and chronic hypercapnic respiratory failure (<xref ref-type="fig" rid="F1">Figure 1</xref>). Thus, patients with frequent exacerbations and asthma-COPD overlap may benefit from the addition of ICS and/or biological therapy (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B21">21</xref>, <xref ref-type="bibr" rid="B23">23</xref>). Patients with frequent exacerbations and chronic hypercapnic respiratory failure may see a reduction in hospitalizations with home NIV use (<xref ref-type="bibr" rid="B61">61</xref>). Another comorbidity should be considered with this phenotype, e.g., antibody deficiency syndrome, which may increase respiratory exacerbations (<xref ref-type="bibr" rid="B62">62</xref>, <xref ref-type="bibr" rid="B63">63</xref>). A retrospective study of patients with COPD and antibody deficiency syndrome with frequent exacerbations showed that appropriate treatment including cycling antibiotics or IgG supplementations reduced respiratory exacerbations from median of four to one exacerbation every year (<xref ref-type="bibr" rid="B64">64</xref>).</p>
<disp-quote>
<p><italic>Summary: Frequent respiratory exacerbations may indicate escalation of treatment (ICS, biologics, azithromycin, roflumilast, home NIV) and further investigation is required to identify other conditions</italic>, e.g., antibody deficiency syndrome, <italic>that may benefit from additional treatment.</italic></p>
</disp-quote>
</sec>
<sec id="S7">
<title>Preserved spirometry at risk for COPD</title>
<p>Recently, this phenotype has been the focus of several investigations because it may reflect a state or condition that precedes COPD and may benefit from early treatment. Woodruff et al. (<xref ref-type="bibr" rid="B4">4</xref>) showed that among individuals with at least 20-pack year of current or former smoking exposure, CAT score &#x003E; 10 (highly symptomatic) was associated with increased respiratory exacerbations and hospitalizations (<xref ref-type="bibr" rid="B4">4</xref>). Pooling individual data of 5 prospective cohorts, Balte et al. (<xref ref-type="bibr" rid="B65">65</xref>) showed that non-obstructive chronic bronchitis (chronic bronchitis with normal spirometry) was associated with respiratory-related hospitalizations and mortality (<xref ref-type="bibr" rid="B65">65</xref>). A metanalysis confirmed that non-obstructive chronic bronchitis was associated with increased all-cause mortality in individuals with current or former smoking exposure but not in people without history of smoking exposure (<xref ref-type="bibr" rid="B5">5</xref>). Air trapping in individuals with current or former smoking exposure is associated with increased medication use, respiratory hospitalizations, progression to COPD, and mortality (<xref ref-type="bibr" rid="B5">5</xref>, <xref ref-type="bibr" rid="B66">66</xref>). Regan et al. (<xref ref-type="bibr" rid="B67">67</xref>) showed that among people with at least 10 pack-years of current or former smoking exposure, 42% have features consistent with obstructive lung disease in the chest CT (<xref ref-type="bibr" rid="B67">67</xref>). Respiratory exacerbations in individuals with normal lung function and current or former smoking exposure are associated with lung function decline and increased all-cause mortality (<xref ref-type="bibr" rid="B60">60</xref>). It is possible that progression to COPD is mediated by lung function decline that results from respiratory exacerbations in individuals with normal lung function. COPDGene investigators have led an effort to expand the definition of COPD to include individuals without spirometric obstruction who are at risk for lung function decline or death (<xref ref-type="bibr" rid="B3">3</xref>).</p>
<p>A recent RCT showed that dual bronchodilator treatment in individuals with smoking history and respiratory symptoms but relative normal spirometry defined as post-bronchodilator FEV<sub>1</sub>/FVC &#x2265; 0.7 and FVC % predicted &#x2265; 70% did not improve respiratory symptoms (<xref ref-type="bibr" rid="B68">68</xref>). However, the lack of efficacy could be due to the fact that bronchodilators have minimal effect on individuals with near normal lung function. It is possible that other types of pharmacotherapy in a different group of individuals should be tested, e.g., inhaled corticosteroids in individuals with non-obstructive chronic bronchitis or respiratory exacerbations. Identifying individuals with normal lung function at risk for COPD and lung function decline may be the focus of future therapeutic trials that will test pharmacological agents which can prevent progression to COPD.</p>
<disp-quote>
<p><italic>Summary: Individuals with normal spirometry and history of smoking who have chronic bronchitis or respiratory exacerbations have increased respiratory-related hospitalizations and mortality. Further research is needed to assess preventive treatment of individuals with normal spirometry but who are at risk of progressing to COPD.</italic></p>
</disp-quote>
</sec>
<sec id="S8">
<title>Preserved ratio impaired spirometry (PRISm)</title>
<p>Preserved ratio impaired spirometry (PRISm), also known as restrictive or unclassified spirometry, is a common spirometric pattern which occurs in 10&#x2013;20% of spirometries (<xref ref-type="bibr" rid="B69">69</xref>&#x2013;<xref ref-type="bibr" rid="B72">72</xref>). PRISm is usually defined as reduced FEV<sub>1</sub> with a normal FEV<sub>1</sub>/FVC (<xref ref-type="bibr" rid="B69">69</xref>) but other definitions applied also refer to a non-obstructive abnormal spirometry (<xref ref-type="bibr" rid="B70">70</xref>). General population studies have reported that it is associated with increased all-cause mortality (<xref ref-type="bibr" rid="B70">70</xref>, <xref ref-type="bibr" rid="B73">73</xref>). Studies in individuals with current or former smoking exposure have shown that PRISm is a heterogenous group with significant symptoms and reduced exercise capacity that includes patients with an FEV<sub>1</sub>% predicted that can range from 44 to 79%, a body mass index (BMI) between 17.2 and 53.8 kg/m<sup>2</sup>, and radiographic emphysema on chest CT that can range from &#x003C; 1% to up to 11% (<xref ref-type="bibr" rid="B69">69</xref>). Individuals with PRISm have higher BMI relative to patients with normal spirometry or obstruction and it has been postulated that PRISm merely is the result of high BMI. However, a landmark study by Jones and Nzekwu (<xref ref-type="bibr" rid="B74">74</xref>) showed that although BMI is inversely associated with FVC and total lung capacity (TLC), obesity in individuals with no respiratory disease is unlikely to reduce FVC below the lower limit of normal (LLN). One study demonstrated that among patients undergoing preoperative evaluation for bariatric surgery with a BMI of &#x2265; 35 Kg/m<sup>2</sup>, only 3% had an FVC &#x003C; LLN (<xref ref-type="bibr" rid="B75">75</xref>). Although a proportion of PRISm could be related only to obesity, it is unlikely that obesity is the sole cause of PRISm in the majority of the cases. Other diseases such as interstitial lung diseases (ILD) can cause PRISm (<xref ref-type="bibr" rid="B72">72</xref>) but the prevalence of ILD is extremely low and thus it is unlikely that ILD accounts for the majority of PRISm cases. Cohorts such as COPDGene, with a PRISm prevalence of 12&#x2013;15%, exclude ILDs (<xref ref-type="bibr" rid="B69">69</xref>, <xref ref-type="bibr" rid="B76">76</xref>).</p>
<p>Most individuals with PRISm likely have obstructive lung disease. Approximately half of individuals with PRISm have TLC on chest CT and &#x003C; 80% predicted or LLN, which likely results from obesity (<xref ref-type="bibr" rid="B69">69</xref>). Obesity is associated with increased FEV<sub>1</sub>/FVC in patients with COPD (<xref ref-type="bibr" rid="B77">77</xref>). Lower TLC secondary to obesity may result in pseudo-normalization of FEV<sub>1</sub>/FVC ratio and underdiagnosis of obstructive lung disease. Our previous work has shown that air trapping in PRISm is associated with increased respiratory exacerbations, progression to COPD, and increased mortality (<xref ref-type="bibr" rid="B78">78</xref>). Unfortunately, no clinical trials have assessed the effect of existing pharmacotherapies on PRISm. Conducting clinical trials in PRISm is a difficult task as PRISm is an unstable phenotype (<xref ref-type="bibr" rid="B76">76</xref>, <xref ref-type="bibr" rid="B79">79</xref>). It has been reported that 25% of individuals with PRISm have COPD on future spirometries, and 16% of those with PRISm had COPD in prior spirometries (<xref ref-type="bibr" rid="B76">76</xref>).</p>
<disp-quote>
<p><italic>Summary: PRISm is a unstable spirometric pattern associated with respiratory symptoms and mortality. Further research is needed to confirm whether individuals with PRISm benefit from existing treatment for COPD.</italic></p>
</disp-quote>
</sec>
<sec id="S9" sec-type="conclusion">
<title>Conclusion</title>
<p>More granular phenotyping of COPD (asthma-COPD overlap, hyperinflation, chronic hypercapnic respiratory failure, frequent respiratory exacerbations) can help to identify patients that respond well to existing treatments, e.g., ICS, home nocturnal NIV. Further research is needed in those individuals at risk for COPD who do not yet have obstructive spirometry (normal spirometry or PRISm) to assess whether treatment can improve outcomes including preventing progression to COPD.</p>
</sec>
<sec id="S10" sec-type="author-contributions">
<title>Author contributions</title>
<p>SF: Conceptualization, Writing &#x2013; original draft, Writing &#x2013; review &#x0026; editing. DG: Supervision, Writing &#x2013; review &#x0026; editing. NT: Supervision, Writing &#x2013; review &#x0026; editing. FS: Writing &#x2013; review &#x0026; editing. JZ: Supervision, Writing &#x2013; review &#x0026; editing. AC: Supervision, Writing &#x2013; review &#x0026; editing.</p>
</sec>
</body>
<back>
<sec id="S11" sec-type="funding-information">
<title>Funding</title>
<p>The authors declare that no financial support was received for the research, authorship, and/or publication of this article.</p>
</sec>
<ack><p>We thank Chrysa Fortis for drawing the figures. We also thank Ms. Kris Greiner for her editing assistance in preparing this manuscript.</p>
</ack>
<sec id="S12" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>SF has received grants from American Thoracic Society and Fisher &#x0026; Paykel and has served as a consultant for Society of Hospital Medicine (SHM). AC has consulted GSK, AstraZeneca, and VIDA Diagnostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="S13" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="S14" sec-type="disclaimer">
<title>Author disclaimer</title>
<p>The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government.</p>
</sec>
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