Introduction

Ambient air pollution (AP) is ubiquitous and adversely affects a large proportion of the world population [1]. The early study of chronic obstructive pulmonary disease (COPD) during the London fog episode in 1952, particularly the adverse effects seen with short-term exposure, stimulated a tremendous amount of epidemiological and experimental research investigating adverse health effects of AP that started with respiratory health indicators but extended to systemic effects and even cancer [2].

COPD is defined as a partly reversible but persistently limited airflow with chronic inflammation of the lung [3, 4]. COPD development can start early in life [5, 6] and progresses slowly until the lung decompensates mostly at advanced ages. The prevalence of COPD in adults older than 40 years of age worldwide ranges between 5 and 19% [7, 8]. Moreover, COPD prevalence does not discriminate between high-income and low-income countries [9]. It is expected that its prevalence will only increase over the next decades [10, 11], due to an increasing number of smokers, particularly in developing countries, and worldwide demographic changes that include a higher proportion of advanced age populations providing long enough latency for this disease to occur. Prognostications from 10 years ago ranked COPD as fifth among the diseases with the highest societal burden by the year 2020 [12]. Already, COPD is the third leading cause of death worldwide [13]. COPD is not easily treated and can cause a substantial economic burden for a society [14]. Currently, the economic and health burdens are underestimated, due to the high rate of co-morbidities with asthma, ischemic heart disease, stroke, pneumonia, and/or lung cancer [15]. Tobacco smoking is the main risk factor for COPD, and its role has been well characterized in disease development, progression, and exacerbation of COPD [16]. However, it is not the only risk factor that should be considered. Not only a less investigated, but also important risk factor is exposure to AP (both ambient air pollutants and indoor AP). The World Health Organization (WHO) estimated that ambient AP was responsible for 3.7 million deaths worldwide in 2012, with 14% of these deaths due to COPD or lower respiratory infections (World Health Organization; Ambient (outdoor) air quality and health; World Health Organization; Geneva: 2014. Fact sheet no. 313). Several recent reviews and original articles conclude that ambient AP exposure is also a notable risk factor for COPD [17•, 18••, 19, 20••, 21,22,23], but the evidence supporting this notion is weak. This review will use several recent systematic reviews and original research papers that focused on the exacerbation and progression of COPD in relation to exposure to ambient air pollutants, such as nitrogen dioxide (NO2), ozone (O3), and particulate matter with a diameter less than 2.5 μm (PM2.5) and less than 10 μm (PM10). The key questions this review article is trying to answer are whether COPD patients are more vulnerable or susceptible to ambient air pollutants and if so, why.

Current Sources and Measures of AP

Ambient AP is a dynamic and complex mixture of anthropogenic (man-made) and natural source-derived pollutants found in varying levels worldwide; the most commonly measured ones in urban areas are particulate matter (PM), ozone (O3), sulfur dioxide (SO2), nitrogen oxides (NO x ), and carbon monoxide (CO). Depending on size, PM is commonly divided into three classifications: coarse particles with diameters of 2.5 to 10 μm (PM2.5–10), fine particles with diameters less than 2.5 μm (PM2.5), and ultrafine particles with diameters less than 0.1 μm (UF). Industrial, agricultural, or domestic heating and traffic-related sources are the main contributors to PM. Traffic-related sources of PM are thought to be responsible for approximately 20% of AP-related mortality in Germany, the UK, and the USA [24].

Coarse particles are often caused by disturbances that disperse crustal materials (dust) and are a problem in the Middle East and other desert areas as constituents of dust storms. Throughout the world, the generation of residential and commercial energy through combustion processes has been linked to premature mortality. This is a large problem in Asia and Africa, where coal is widely used for heating and cooking and produces high levels of fine PM [24]. A recent review of global premature mortality due to outdoor AP found that fine PM (PM2.5) is estimated to cause 3.3 million deaths per year worldwide [24].

The potency of PMs in causing adverse health impacts is dependent, in part, on their ability to deposit in the airways and the particle surface characteristics [25].

With the growth of urban centers and the advent of global climate change, it has been estimated that ground-level ozone (ozone smog) will become an increasingly greater health hazard. Ozone smog forms when nitrogen oxides and volatile organic compounds from vehicle, power plants, and other sources mix with sunlight and heat; specifically, increasing temperatures contribute strongly to ozone smog formation. Other critical pollutants, such as SO2, NO x , and CO, are also produced by fossil fuel combustion from automobiles and power plants and will continue to contribute to AP in large urban areas, especially in densely populated cities like those in Asia and Africa [24, 26].

During the past five or six decades, a vast amount of studies documented the adverse health effects of AP affecting mortality, health-related quality of life, and a broad spectrum of diseases such as cardiovascular diseases, respiratory health, and cancer [27, 28].

Epidemiological Designs to Study AP Exposure and COPD

There are two major epidemiological approaches that are being used to explore associations between ambient AP exposure and COPD: the vulnerability approach (Fig. 1) and the onset of COPD approach. While the vulnerability approach compares adverse health events between COPD patients and the general population, the COPD onset approach relies solely on studies of general populations. This review is referring to results that employed the vulnerability approach. Nevertheless, a brief summary of studies investigating the onset of COPD will add to the understanding of how and why both approaches are to be considered separately.

Fig. 1
figure 1

Epidemiological study approaches to investigate vulnerability of COPD patients to ambient air pollution

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AP and the Onset of COPD

Briefly, the onset of COPD approach includes whole populations that are followed up and randomly selected subjects from the general population, who are free of a COPD diagnosis. These subjects are then being followed over an extended period of time. A recent systematic review included eight morbidity and six mortality studies, which were very heterogeneous with regard to several methodological aspects such as exposure assessment, definition of COPD cases, and study design [21]. The authors concluded that the evidence for chronic effects of AP on prevalence and incidence of COPD was suggestive, but not conclusive. Additionally, an editorial accompanying the review supported this notion [29]. A more recent combined analysis of several European cohorts, which used an advanced exposure assessment method—land use regression (LUR) models developed in the ESCAPE project—confirmed the vague statement of previous systematic reviews [22]. However, a systematic review and meta-analysis of recent time series studies from China showed statistically significant associations between ambient AP exposure of PM10, SO2, and NO2 and COPD mortality for same-day exposure (lag0) and the exposure 3 days before (lag3) [20••].

Methodologically, the COPD onset approach is quite different from studying the increased vulnerability of those suffering from COPD.

Are COPD Patients Vulnerable to Ambient AP?

The potential vulnerability of COPD patients to AP can be assessed by documenting over extended periods

  1. (A)

    All-cause mortality

  2. (B)

    COPD mortality

  3. (C)

    COPD hospitalization and emergency visits

  4. (D)

    Lung function and respiratory symptoms (Fig. 1).

This review will summarize the current state of the science for each of the four progressive health outcomes in COPD. We will use the most recent systematic meta-analysis or general reviews and will add newer results after the last review was published. The key findings of selected studies are shown in Supplemental Table 1 .

All-Cause Mortality

A large study in Rome [30] followed 145,681 COPD patients age 35+ years for 4 years. The association between short term exposure to daily AP and daily mortality was modeled in both COPD subjects and everyone else in the city over 35 years of age without any COPD diagnosis (1,710,557 subjects). COPD patients showed higher mortality rates from PM2.5, PM10, and NO2 exposure compared with subjects without COPD. Especially strong was the difference for PM10 which had a five times larger effect estimate for total mortality. Additionally, effect estimates were three to seven times higher in the COPD subjects, for respiratory causes of death depending on which air pollutant and lag was being assessed.

A similar time series study of COPD subjects in Barcelona also reported increased all-cause mortality in relation to NO2 [31]. A further study with COPD patients over 35 years in Barcelona showed increased mortality risk of 1.11 (95CI 1.00–1.24) with increased PM10 per IQR, but not for ozone and CO [32].

COPD Mortality

Several systematic reviews assessed the role of short-term exposure to ambient AP on COPD mortality [17•, 20••, 33, 34]. One study summarized the findings of literature published between 1995 and 2015 [33], another updated this until March 30, 2016 [34], another one until April 15, 2015 [20••], and the last until May 2011 [17•]. We decided to restrict to systematic reviews published during the last 3 years, since these reviews were not only different in the time period they covered, but also in terms of selection criteria and search terms (major ambient AP versus PM2.5 only; written in English only papers versus English and Chinese database usage; COPD mortality alone versus a combined category that included both COPD mortality and hospitalizations). The most recent review [33], identified 11 studies addressing COPD mortality; however, it did not include the most recent literature since it stopped its search in 2015. This meta-analyses estimated pooled effects for COPD-related mortality of 1.048 (95% CI 1.019–1.078) for PM2.5 based on five studies. The other six meta-analyses provided summary estimates for NO2 of 1.03 (95% CI 1.016–1.045). The review with the latest search date (March 30, 2016) identified 12 papers for COPD mortality only and six studies for combined COPD mortality and hospitalization [34]. This review not only relied on English databases, but also included a large Chinese database (CNKI). Overall, there was a significant association between short-term exposure and the risk of COPD exacerbation for all gaseous and particulate pollutants. An increment of 10 μg/m3 for each pollutant was associated with increased risks for PM10 [1.017 (95% CI 1.012–1.022)], PM2.5 [1.024 (95% CI 1.005–1.043)], NO2 [1.045 (95% CI 1.028–1.062], SO2 [1.006 (95% CI 1.001–1.012)], ozone[(1.028 (95% CI 1.011–1.044)]—whereas the increment for CO was 100 μg/m3—and CO [1.008 (95% CI 1.004–1.013)]. This review was of particular importance, since it included sensitivity analyses stratified by geographical location and it showed stronger effects for Asian than non-Asian countries.

Another review included publications written only in English before April 15, 2015 and reported increase of COPD mortality of 2.5% (95% CI 1.5–3.5%) and 3.1% (95% CI 1.6–4.6) increased COPD hospitalization per 10 μg/m3 increase in PM2.5 [20••]. An earlier review [17•] found a statistically significant increased risk for COPD admission of 2.4% (95% CI 1.00–3.73%) per 10 μg/m3 PM2.5 but only for subjects older than 65 years and after excluding asthmatics, while the effect estimate for COPD mortality was 2.86% (95% CI − 0.12–5.93%).

The MED-PARTICLE Study investigated the specific cause of death associated with short-term exposure to PM2.5 and PM2.5–10 in Southern Europe for the period of 2001–2010 [35]. An increased 10 μg/m3 PM2.5 exposure was associated with a 2.53% (95% CI − 0.01–5.14) increase of COPD death, which was higher than any other cause-specific mortality. This was further supported by a positive association of PM2.5 per 10 μg/m3 with COPD as cause of death [0.38% (95% CI 0.23–0.53)] compared to other common causes of death reported in a large nationwide time series analysis of 272 Chinese cities [36]. Most of the effect estimates were given for a fixed increment of 10 μg/m3, which makes it difficult to compare the effects across different pollutants. Another major problem is related to use COPD mortality as an outcome of interest, because of its variation in the coding of COPD mortality used by original papers and also in systematic reviews. Thus, it makes it difficult to compare the results across regions and papers.

COPD Hospitalization and Emergency Visits

The most recent systematic review on the influence of ambient AP on COPD hospitalization and emergency visits identified 26 papers published between 1995 and 2015 [33]. COPD hospitalization and emergency room visits were affected by an exposure to air pollutants, a 2.5% (95% CI 1.6–3.4%) increase per 10 μg/m3 of PM2.5, a 4.2% (95% CI 2.5–6.0%) increase per 10 μg/m3 for NO2, and a 2.1% (95% CI 0.7–3.5%) increase per 10 μg/m3 for SO2. Unfortunately, these effect estimates cannot be compared, because the fixed increment of 10 μg/m3 does not reflect similar toxicities of each air pollutant. Another even larger systematic review identified 59 studies on ambient air pollutants (PM2.5, PM10, NO2, SO2, CO, O3) and COPD exacerbations (hospital admission and/or COPD mortality) from English and Chinese databases in studies published before March 30, 2016 [34]. Out of the 59 included studies, the majority (41 studies) were focused on COPD hospital admission while 12 were modeled COPD mortality only and six both. The stratified analysis for COPD hospital admission showed the following effect estimates: 1.0% (95% CI 0.0–1.0%) for PM2.5, 2% (95% CI 1–2%) for NO2, and 0% (95% CI 0–0%) for ozone for an increment of 10 μg/m3, but 0% (95% CI 0–0%) for CO per increment of 100 μg/m3. Two additional systematic reviews and meta-analyses focused on short-term exposure effects of PM2.5 and COPD hospitalization and mortality [17•, 20••]. Based on a literature search that ended April 15, 2015, 12 studies of COPD hospitalization were included in the meta-analysis. A 10-μg/m3 increase in daily PM2.5 (lag days 0–7) was associated with a 3.1% (95% CI 1.6–4.6%) increase in COPD hospitalization [20••]. The summary estimates for PM2.5 exposure and COPD hospitalization based on studies published before May 2011 [17•] however were smaller [0.96% (95% CI − 0.63–2.58%)] and not statistically significant. However, a sensitivity analysis restricted to subjects ages 65+ years without asthma did find a statistical significant association with PM2.5 [2.36% (95% CI 1.0–3.73%)] in the systematic review [17•].

A further systematic review only including East Asian studies also found increased COPD hospitalization with PM10, SO2, and O3 exposures [37].

Reviews included different regions of the world, several air pollutants, and employed various selected lags ranging from same-day exposure (lag 0) to 7-day exposure preceding outcome measurements. Nevertheless, all systematic reviews consistently found increasing COPD hospitalization/emergency visits with increasing PM2.5 and PM10 exposures, but only in the most recent reviews, effect estimates were found to be statistically significant. Several reasons might contribute to the increasing body of evidence for the positive association between ambient air pollution exposure and hospital admission for COPD: more studies and larger sample size as well as more studies from Asia, which showed higher effect estimates compared to some European studies.

Lung Function and Respiratory Symptoms

A systematic review identified 25 panel studies published between 1993 and February 1, 2016 [18••]. Of these 17 studies included COPD patients only, the others also followed asthmatics, patients with ischemic heart disease, and apparently healthy subjects; these studies were conducted mainly in Europe, North America, and East Asia. Meta-analysis of ten studies with lung function tests showed a small but statistically significant decline of forced expiratory volume in 1 s (FEV1) (− 3.38 mL, 95% CI − 6.39 to − 0.37) and peak expiratory flow rate (PEF) (− 0.61 L/min, − 1.20 to − 0.01) per 10 μg/m3 increment of PM10 followed the exposure after a maximum of 2 days. Respiratory symptoms such as breathing problems, shortness of breath, or respiratory symptoms score increased with increasing exposure to PM10 in most of the studies. A summary estimate for these eight studies, which reported effects on respiratory symptoms, could not be calculated because of the heterogeneity of the outcome definition and scale of symptom scores. The results for effect of NO2 on lung function and respiratory symptoms were mixed and more heterogeneous than the findings for PM10. Unfortunately, this review did not compare AP effects in COPD patients with those in other panel participants such as cardiac compromised patients or healthy subjects. Not included in this systematic review was a panel study that monitored 23 stable COPD patients in Beijing for a 9-month period and measured extremely high AP levels monitored at one single site with an interquartile range (IQR) of 76.5 m3 for PM2.5, 75.0 μg/m3 for PM10, and 45.7 μg/m3 for SO2. They found a statistically significant incremental change in IQR for each pollutant and an increase of respiratory symptoms such as sore throat, cough, sputum production, wheeze, and dyspnea [38]. Furthermore, there was a statistically significant increase in exhaled nitric oxide (FeNO) and exhaled hydrogen sulfide (FeH2S) associated with increases in all included air pollutants.

Vulnerability of COPD Patients to Ambient Air Pollutants by Age and Geography

A systematic review and meta-analysis of 108 papers, targeting subpopulations that are especially vulnerable to ambient AP exposure, found strong and consistent evidence for a higher vulnerability in the elderly [39]; however, disease-specific vulnerability was not studied in this review.

Age-stratified analysis of AP effects on COPD exacerbation showed mixed results. The most recent comprehensive review [34] highlighted that COPD patients ages 65+ years are more vulnerable to ambient AP exposure than younger COPD patients, which was also reported by a previous review [17•]. However, a similar review [20••] did not support this notion. A further more extensive review of ambient AP health effects characterized the elderly as a vulnerable subgroup for particulate matter exposure; in this case, the elderly included COPD patients [40].

Regarding regional differences, one review [34] collected a sufficiently large number of studies located in Asia and other parts of the world. In these studies, higher effect estimates of AP exposure on COPD exacerbation were reported for Asian patients, which can be interpreted as a higher vulnerability of COPD patients from Asia and/or as the effect of a higher exposure to air pollutants and/or as a consequence of different air pollutant mixtures.

Potential Mechanisms for Increased Vulnerability of COPD Patients to Ambient AP

The main underlying mechanisms for adverse health effects from ambient AP exposure are related to oxidative stress and inflammation [32, 41,42,43]. Apart from the fact that particles can translocate into the blood stream and create vascular dysfunction with potential systemic effects, air pollutant-related oxidative stress can directly damage the epithelium of the airways and reduce the immune response [44]. A further potential mechanism for a higher vulnerability of COPD patients to ambient air pollution exposure is an increased direct induction of inflammation of the damaged lungs of COPD patients which can promote a further reduction of pulmonary function in COPD patients [45]. Finally, COPD patients have more particle deposits in the lung possibly due to a reduced clearance of particles from the lung which may further increase the vulnerability of COPD patients to ambient air pollutant exposure, particularly ambient particles [42, 44, 45].

Improved Air Quality and Changes of Prevalence and Exacerbation of COPD

A few studies indicated that a decline in AP levels is associated with a lower prevalence of respiratory symptoms, COPD and COPD-related biomarkers ([46, 47]. A cohort of more than 2000 women, aged 55 years at baseline, in Germany was followed for 20 years [47]. The decline of ambient air pollutants (PM10, NO2) was associated with a reduction in self-reported COPD-related symptoms and spirometry confirmed COPD. These temporal changes need to be considered with caution because the improved air quality is not the only characteristic that changed over time. Nevertheless, the authors concluded that a reduction in AP appears to attenuate respiratory aging in these women.

Conclusions and Uncertainties of Summarized Epidemiological Findings

While numerous studies and systematic reviews have been published, which address the effects of exposure to ambient air pollutants on COPD exacerbation that could be used to evaluate the specific vulnerability of COPD patients to air pollutants, these studies differ in many aspects. The diagnosis of COPD differed substantially across these studies. The overlap with asthma is insufficiently documented, and asthmatics are included in the analysis in many studies of COPD outcomes. COPD mortality as the outcome of interest is difficult to precisely assess since COPD might be comorbid with many other common chronic diseases making it uncertain whether AP exposures exacerbated COPD or other chronic disorders. Another concern is whether exposure assessment of air pollutants was very selective since the ambient air pollutants addressed strongly varied across the studies. In addition, the epidemiological study designs used to evaluate the AP effects in COPD patients were very different and included cohorts, time series, case-crossover, and panel studies.

Despite these differences, overall studies support that AP differentially affects COPD patients more strongly and support the notion that COPD patients are a vulnerable subgroup that needs special protection from breathing highly polluted air.