REVIEW URRENT C OPINION

Predictors of chronic obstructive pulmonary disease exacerbations Takeo Ishii a,b and Kozui Kida a,b

Purpose of review A frequent-exacerbation phenotype of chronic obstructive pulmonary disease (COPD) exists that is independent of disease severity. Establishment of methods to predict ‘frequent exacerbators’ is critical. The purpose of this review is to critically assess the recent literature regarding predicting COPD exacerbations, and to provide recommendations for future research. Recent findings Although there are many studies in which inflammatory biomarkers have been used in an attempt to predict future exacerbations, it is likely that these biomarkers represent a consequence rather than the cause. Genetic predictors are involved in causal pathways. Thus, genetics should be investigated in order to understand the exacerbation mechanism and to develop new therapeutic approaches. Some single nucleotide-type genetic polymorphisms are associated with exacerbations, and the individuals with genotypes protective against infection are less susceptible to exacerbations. In contrast, we reported that loss of Siglec-14, a lectin likely involved in host defense, was associated with a reduced COPD exacerbation risk. Summary We should take into consideration that a protein involved in host defense such as Siglec-14, that could also trigger exaggerated response, might also generate unwanted local and systemic inflammation, which could be detrimental to a host and could generate COPD with a frequent-exacerbation phenotype, its progression, and its comorbidities. Keywords chronic obstructive pulmonary disease pathogenesis, copy number variants, infection, inflammation, lectins

INTRODUCTION The Global Initiative for Chronic Obstructive Lung Disease (GOLD) consensus report proposed a new classification system for chronic obstructive pulmonary disease (COPD) in order to more comprehensively assess disease severity that incorporates symptoms with either dyspnea or health status measures, in addition to a history of COPD exacerbations and airflow limitation [1]. As the new GOLD classification is a better predictor of future exacerbations than the old GOLD classification [2 ,3 ], it could also lead to better treatments for stable COPD with respect to preventing exacerbations. Exacerbations are a leading cause of mortality from and a major cost driver of COPD [4]. Many new drugs, including roflumilast in the United States, are being approved because of their capacity to reduce exacerbations [5]. Respiratory infections are thought to be common causative agents for COPD exacerbations [6] &

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and were thus investigated. However, little was known about host conditions of COPD patients, until it was reported recently that a frequent-exacerbation phenotype of COPD exists that is independent of disease severity [7] and is stable [8 ]. This phenotype is related not only to COPD progression but also to COPD pathogenesis, because this phenotype possibly begins before a patient, particularly a smoker, is diagnosed with COPD. Fletcher and Peto [9] demonstrated the natural &

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a Respiratory Care Clinic, Nippon Medical School and bDepartment of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan

Correspondence to Takeo Ishii, MD, PhD, Respiratory Care Clinic, Nippon Medical School, 4-7-15-8F, Kudan-minami, Chiyoda-ku, Tokyo 102-0074, Japan. Tel: +81 3 5276 2325; fax: +81 3 5276 2326; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:138–145 DOI:10.1097/MCP.0000000000000031 Volume 20  Number 2  March 2014

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Chronic obstructive pulmonary disease exacerbations Ishii and Kida

KEY POINTS  Genetic variations related to a frequent-exacerbation phenotype such as the SIGLEC14 null allele would be useful to predict the risk of exacerbations in COPD.  In the process of evolution, Siglec-14 was needed to protect humans against bacterial infection, but may induce unwanted and chronic inflammation in COPD in the postmodern human with long life-expectancy, which possibly leads to the emergence of a frequentexacerbation phenotype.  Antibacterial but proinflammatory molecules such as Siglec-14 can cause repetitive exacerbations and excessive inflammatory responses as ‘repetition of vicious cycles’, which could lead to COPD, its progression, and its comorbidities.

course of COPD, the ‘Fletcher–Peto curve’, and they showed that the expiratory airflow limitation, defined as forced expiratory volume in 1 s, declines with age throughout adulthood, and that smoking, without the effect of mucus hypersecretion, accelerates its decline (Fig. 1a). Subsequently, Burrows [10] indicated that some COPD individuals might have exacerbation and remission periods with each episode leading to a progressive loss of function (Fig. 1b) [11]. Further, before smokers are diagnosed with COPD, severe inflammation secondary to infection in the lungs, due to pulmonary infection during smoking, might also affect the development of emphysema and other airway diseases related to

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COPD in individuals with a frequent-exacerbation phenotype, especially if this phenotype is mainly determined by genetics. Thus, we now know that a ‘frequent-exacerbation’ phenotype exists that affects the pathogenesis and progression of COPD, thus necessitating clarification of the factors that could help predict this phenotype.

THE STATE OF CURRENT RESEARCH REGARDING EXACERBATIONS: FACTORS OBSERVED IN CLINICAL SETTINGS The frequent-exacerbation phenotype was reported to be associated with an elevated white-cell count, prior exacerbations, a history of gastroesophageal reflux, and severity of airway obstruction [7]. Regarding inflammatory biomarkers, a study involving a larger population showed that simultaneous elevation of C-reactive protein level, fibrinogen level, and leukocyte count were associated with an increased exacerbation risk [12 ]. It was also found that higher baseline levels of E-selectinpositive endothelial microparticle (EMP), which is not only a marker of endothelial dysfunction but also considered to have a role in inflammation [13], may indicate which COPD patients are susceptible to an exacerbation [14 ]. As EMPs are elevated in COPD and are positively related to the severity of emphysema, EMPs could be a biomarker of COPD itself and the frequent-exacerbation phenotype [15 ]. &&

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FIGURE 1. Possible ‘natural histories’ of COPD. (a) A Fletcher–Peto curve, presented in the GOLD guideline. (b) ‘Natural histories’ that can lead to severe COPD in various manners, as described by Burrows [10]. Some with a frequent-exacerbation phenotype may have repetition of exacerbation and remission leading to progression of COPD, shown as ‘B’ [11]. COPD, chronic obstructive pulmonary disease. (a) Reproduced with permission from [9]; (b) reproduced with permission from [10] (Copyright Elsevier). 1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

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Various clinical components other than the pulmonary function test, which assesses COPD severity, could affect exacerbation susceptibility. A greater degree of lung emphysema and an increased airway wall thickness were associated with COPD exacerbations [16]. Regarding exercise capacity, a lower daily step count and shorter distance in the 6-min walk test predicted future exacerbations and COPD-related hospitalizations [17 ]. Baseline scores on the COPD Assessment Test (CAT), an eight-item questionnaire designed to assess and quantify the impact of COPD symptoms on health status, are also elevated in frequent exacerbators [18 ]. The assessment of prior exacerbations is useful for predicting a frequent-exacerbation phenotype. As mentioned above, a new GOLD classification system [1], which assesses COPD exacerbation history, better predicted future exacerbations [2 ,3 ], and the occurrence of every new severe exacerbation requiring hospitalization worsened the disease course and increased the risk of a subsequent exacerbation [19 ]. We also found that among the three multidimensional assessment systems [Body Mass Index, Obstruction, Dyspnea, Exercise (BODE); Dyspnea, Obstruction, Smoking, Exacerbation (DOSE); and Age, Dyspnea, Obstruction (ADO) indices], the DOSE index, in which prior exacerbations are taken into account, was a better predictor of COPD exacerbations [20 ]. It was also reported that this frequent-exacerbation phenotype is associated with comorbidities including not only gastroesophageal reflux, but also depression [21 ], cognitive dysfunction [22 ], and pulmonary arterial enlargement [23 ]. &

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THE STATE OF CURRENT RESEARCH ON EXACERBATIONS: GENETIC FACTORS DECREASING IMMUNITY The frequent-exacerbation phenotype is relatively stable [7], which suggests the presence of contributing genetic factor(s). Several reports exist regarding the association between exacerbation susceptibility and some gene variations, including surfactant protein B [24], mannose-binding lectin [25], and chemokine ligand 1 [26]; the proteins coded by these genes are a surfactant protein, a lectin that acts as a pattern-recognition receptor in serum, and a chemokine, respectively, and they mainly have the capacity to protect against bacteria or viruses. The genetic variations that increase this capacity are thought to reduce susceptibility to infection, and thus COPD exacerbations. It was also reported that an immunoglobulin G titer for a periodontitis-related antibody was related to exacerbation frequency [27 ]. Further &&

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investigation is needed regarding the role of acquired immunity and aspiration pneumonia in COPD exacerbations, as well as the role of vaccinations.

A NEW PREDICTION FACTOR FOR AN EXACERBATION-PRONE PHENOTYPE: SIGLEC-14, AN ANTIBACTERIAL, PROINFLAMMATORY LECTIN Siglecs are a family of sialic acid-binding immunoglobulin-type lectins expressed mainly on innate immune cells [28]. Siglec-14, a family member with an activating signaling property, and Siglec-5, an inhibitory counterpart with an extensive sequence identity to Siglec-14, are both expressed on myeloid cells. Siglec-14 likely contributes to host protection by eliciting inflammatory responses, which might inadvertently lead to COPD exacerbation (Fig. 2a) [29 ,30]. In humans, the ancestral (wildtype) SIGLEC gene cluster has both SIGLEC14 and SIGLEC5 genes in tandem, whereas a derived (SIGLEC14-null) allele harbors a single SIGLEC14/5 fusion gene, whose product is identical to Siglec-5 at the amino acid level, but without the SIGLEC14 allele [30] (Fig. 2b); this genetic variation is detected as a copy-number variant (CNV). A loss of Siglec-14 could result in attenuated immune responses against pathogenic bacteria that express sialic acids, such as non-typeable Haemophilus influenzae (NTHi), a major cause of COPD exacerbations [31] that expresses lipooligosaccharides, which contain sialic acids [32 ]. We found that NTHi interacts with Siglec-14 in order to enhance proinflammatory cytokine production, and that a loss of Siglec-14, because of SIGLEC14null allele homozygosity, is associated with a reduced COPD exacerbation risk [29 ]. Siglec-14 and its downstream signaling pathway facilitate the ‘infection–inflammation–exacerbation’ axis of COPD disease progression, although it could have a role in host protection against bacteria, such as the above-mentioned mannose-binding lectin. &

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NEW VIEWPOINTS FROM A SIGLEC-14 STUDY: LECTINS AND PROTEINS RELATED TO GLYCOSYLATION As exacerbations are mainly elicited by a viral or bacterial infection, we could speculate that genetic variations of pattern recognition molecules, including Toll-like receptors, NOD-like receptors, are associated with a frequent-exacerbation phenotype. Mannnose-binding lectin is a kind of collectin that belongs to Ca2þ-dependent lectins and is a soluble pattern recognition receptor. Collectins have critical roles in innate immunity and also Volume 20  Number 2  March 2014

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(a) Wild type

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FIGURE 2. CNVs in SIGLEC14 and a frequent-exacerbation phenotype in COPD. (a) Possible mechanism behind the association between the SIGLEC14 genotype and a frequent-exacerbation phenotype in COPD. Siglec-14, a family member with an activating signaling property, and Siglec-5, an inhibitory counterpart with extensive sequence identity to Siglec-14, are both expressed on myeloid cells. Siglec-14 likely contributes to host protection by eliciting inflammatory responses, which might inadvertently lead to COPD exacerbation. (b) Schematic diagram of SIGLEC5 and SIGLEC14 genes as CNVs. In humans, the ancestral (wildtype) SIGLEC gene cluster has both SIGLEC14 and SIGLEC5 genes in tandem, whereas a derived (SIGLEC14-null) allele harbors a single SIGLEC14/5 fusion gene, whose product is identical with respect to Siglec-5 at the amino acid level, without the SIGLEC14 allele. CNVs, copy-number variants; COPD, chronic obstructive pulmonary disease; NTHi, non-typeable Haemophilus influenzae. (a) Reproduced with permission from [29 ]; (b) modified with permission from [30]. &

include surfactant A and D. As genetic variations of surfactant protein D are associated with emphysema in white and Japanese populations [33 ,34 ], as well as with COPD progression [35 ], their relation to exacerbation is also anticipated. Siglec-8 is an inhibitory member of the Siglec family of lectins expressed on eosinophils and mast cells, and its genetic variation is associated with bronchial asthma [36]. Eosinophilic exacerbation was observed in COPD [37,38], and evidence of an &

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allergic phenotype was associated with the risk of COPD exacerbations [39]. Thus, not only Siglec-14 but also other Siglecs including Siglec-8 have possible roles in the pathogenesis of various exacerbations types, that is, bacterial, allergic, and possibly viral. Genes for most of these Siglecs are clustered on chromosome 19q13.3–4 [40], and this region was shown to be relatively adjacent to a susceptibility locus for early-onset COPD by a linkage analysis [41] and also for COPD by a genome-wide association

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study, which had a larger population [42 ]. Siglecs could also have critical roles in COPD pathogenesis through modification of exacerbation susceptibility. Siglecs are thought to have roles in recognizing ‘self’ by using sialic acids that are expressed on host cell surfaces [28]. However, sialic acid-binding viruses such as influenza virus utilize sialic acids on human cell surfaces to infect these cells [32 ]. Therefore, proteins related to glycosylation might be also good candidates for a pathogenesis investigation. Heterozygous Fut8 (a1,6-fucosyltransferase) knock-out mice exhibited an emphysema-prone phenotype [43 ]; also as a genetic variation that caused an amino-acid change in FUT8 was associated with emphysema in humans [44], and patients with lower serum Fut8 activity experienced more frequent exacerbations [45 ]. Proteins related to glycosylation such as Fut8 might have some roles in exacerbation susceptibility. &&

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NEW VIEWPOINTS FROM A SIGLEC-14 STUDY: COPY NUMBER VARIANTS, EVOLUTION, AND ETHNIC DIFFERENCES A null variant of SIGLEC14 could be considered as a CNV (Fig. 2b). Compared to single nucleotide polymorphisms, CNVs can powerfully influence a person’s susceptibility to disease [46], including COPD exacerbations. For example, a CNV of b-defensin, an antibacterial peptide, was associated with COPD, which led to the hypothesis that b-defensin was involved in the pathogenesis of COPD through modification of exacerbation susceptibility [47]. The expression of sialic acids by NTHi likely represents an evolutionary process that has the advantage of mimicking sialic acid-based ‘selfassociated molecular patterns’, which are normally recognized by inhibitory Siglecs such as Siglec-5. The cross-recognition by Siglec-14 (activating counterpart) probably represents a host evolutionary response to this bacterial evolutionary development. However, such a host response may also generate unwanted inflammation, which is detrimental to a host with a chronic disease such as COPD (Fig. 2a) [29 ], as human life expectancy at birth has doubled to tripled during the last 200 years because of industrialization [48]. East/southeast Asia is considered to be the epicenter of cross-species transmission of influenza viruses from migratory birds (natural host) to humans. An influenza infection frequently leads to a secondary NTHi infection that often results in more fulminant symptoms and increased mortality, likely because of ‘cytokine storm’. A lack of Siglec-14 might mitigate the cytokine storm that is triggered by a secondary NTHi infection. This may explain &

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why the null allele frequency of SIGLEC14 is high in Asia, despite the potential risk of attenuated immune control from other bacterial pathogens that display sialic acids (T Angata 2013, personal communication). In industrialized countries, the frequency of exacerbations is higher in whites [49,50] as compared to that of Japanese populations [20 ,51 ]. This difference regarding exacerbation frequency between societies could be partially explained by ethnic differences in the null allele frequency of SIGLEC14 [30]. As differences in allele frequency of various genetic variances that are related to a frequent-exacerbation phenotype could induce differences in exacerbation frequency among social groups, ethnic differences are a new and critical viewpoint for determining the genetic factors related to a frequent-exacerbation phenotype. Macroscopic evolutionary changes are also important. Descent of the larynx from chimpanzees to humans has caused the emergence of sleep apnea and gastroesophageal reflux [52,53], and these two diseases are related to exacerbation risk [7,54]. Thus, further study is necessary regarding the genetic factors related to anatomical issues. Although humans acquired the SIGLEC14 gene during evolution, mice do not have this gene [55 ]. Studies using gene-knockout mice have had much impact on COPD research. However, we must be careful as human have genes that mice do not, such as Siglec-14, which could be a cause of COPD as well as its exacerbations from an evolutionary point of view. &

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NEW VIEWPOINTS FROM A SIGLEC-14 STUDY: LONGEVITY AND UNWANTED INFLAMMATION During evolution, Siglec-14, which was necessary to protect humans from bacterial infections in a preindustrialized era in which antibiotics were not yet in existence, may induce unwanted chronic inflammation with a chronic disease such as COPD, as the human life expectancy at birth has increased during the industrialized era [48], which possibly led to the emergence of a frequent-exacerbation phenotype. Severe, excessive inflammation, that surpasses the amount necessary for the protection against infectious pathogens, is one of the COPD exacerbation characteristics and is treated with a systemic steroid as standard therapy, which is different from that of a pneumonia or acute bronchitis treatment. As lipopolysaccharide (LPS) induced matrix metalloproteinase (MMP)-9 in our COPD-exacerbation mouse model [56 ] and MMP-12 protein expression in alveolar macrophages induced by LPS was correlated to the severity of emphysema in humans [57 ], &

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Chronic obstructive pulmonary disease exacerbations Ishii and Kida

excessive expression of proteases including MMPs caused by repetitive exacerbations might cause COPD progression.

CONCLUSION The frequent-exacerbation phenotype was reported recently [7], and its association with inflammatory markers was mainly studied. However, in order to determine the prediction markers and targets for therapeutic intervention so as to treat COPD exacerbations and limit disease progression, we should investigate causal genetic markers such as SIGLEC14 in future research. During evolution Siglec-14 was necessary to provide protection against bacterial infections, but it may induce unwanted and chronic inflammation in COPD during an era with a longer life expectancy, which has possibly led to the emergence of a frequent-exacerbation phenotype. We speculate that this phenotype not only causes COPD progression but also might be involved in the pathogenesis of

COPD itself. We have discussed the hypothesized role of Siglec-14 in the pathogenesis of COPD as a whole (Fig. 3) [31]. Antibacterial but proinflammatory molecules, such as Siglec-14, would cause repetitive exacerbations and excessive inflammatory responses, or ‘repetition of vicious cycles’, which could lead to local and systemic chronic inflammation. Therefore, this chronic, but repetitive and intermittent, inflammation could be a cause of the frequent-exacerbation phenotype of COPD (especially GOLD C and D), its progression, and its comorbidities (athrosclerosis [58 ], osteoporosis [59 ], and possibly cancers). As a loss of Siglec-14, because of SIGLEC14-null allele homozygosity, is associated with a reduced risk of exacerbation and airflow obstruction in COPD [29 ], this study is a good model to help determine a genetic predictor for the susceptibility to exacerbations through investigation of CNVs regarding the ‘infection–inflammation–exacerbation’ axis. A search for the causal genes of a frequent-exacerbation phenotype may lead to the discovery of exacerbation predictors and also to the pathogenesis of COPD. &&

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Initiating factors Impaired innate lung defense

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Excessive inflammatory response

Acknowledgements We would like to thank Dr Takashi Angata for personal communications and general discussions, and Dr Peter D Pare´ for general discussions. This work was supported by the Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation (NIBIO), Japan [K.K.]. Editage checked this article to ensure an acceptable standard of English. Conflicts of interest There are no conflicts of interest.

Local and systemic chronic inflammation w/ excess of proteases

COPD w/ frequent exacerbations, its progression, and its comorbidities (atherosclerosis, osteoporosis, cancers, ...)

FIGURE 3. The hypothesized role of an antibacterial but also proinflammatory molecule, Siglec-14, in the pathogenesis of COPD as a systemic disease. The antibacterial but proinflammatory lectins such as Siglec-14 may induce unwanted and chronic inflammation in COPD in a repetitive manner, which corresponds to a ‘frequentexacerbation phenotype’. This phenotype causes ‘local and systemic’ chronic inflammation with excessive expression of proteases (e.g., MMP-9 and MMP-12), which leads to the emergence of COPD, its progression, and its comorbidities including atherosclerosis, osteoporosis, and cancers. COPD, chronic obstructive pulmonary disease; NTHi, non-typeable Haemophilus influenzae. Modified with permission from [31].

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Predictors of chronic obstructive pulmonary disease exacerbations.

A frequent-exacerbation phenotype of chronic obstructive pulmonary disease (COPD) exists that is independent of disease severity. Establishment of met...
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