Description of the condition

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline defines chronic obstructive pulmonary disease (COPD) as a common, preventable and treatable disease that has a significant detrimental impact on quality of life, and poses a substantial and growing economic and social burden (GOLD 2020). As a leading cause of global mortality, approximately three million deaths are attributed to COPD every year (WHO 2018). People with COPD have a high frequency of respiratory complications and systemic comorbidities. These comorbidities, including cardiovascular diseases, osteoporosis, depression and gastroesophageal reflux disease (GERD), may potentiate the severity of COPD, leading to an increase in acute exacerbations (Wedzicha 2013).

The latest GOLD guidelines define COPD exacerbation as "an acute worsening of respiratory symptoms that results in additional therapy" (GOLD 2020). The economic impact of COPD exacerbations is substantial, since COPD exacerbations are linked to mortality, morbidity, and hospitalisations (Perera 2012). Therefore, effective COPD management should aim to relieve presenting symptoms, prevent future exacerbations and delay disease progression (Woodruff 2015), with an emphasis on a comprehensive care plan for COPD and associated comorbidities (Barnes 2013; Wedzicha 2013).

GOLD specifies the diagnostic criteria for COPD as a post bronchodilator forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) ratio of less than 0.70 (GOLD 2020). However, defining COPD by these lung function test indices alone may imply that COPD is a homogenous condition. In fact, COPD is a heterogeneous group of conditions with a wide array of symptoms and therapeutic responses towards conventional treatment, and prognoses and comorbidities associated with COPD vary. This heterogeneity cannot be explained by lung function alone, and groups of people with COPD who express particular characteristics can be regarded as having different phenotypes (Han 2010). The ultimate goal of identifying COPD phenotypes is to develop effective and people‐oriented treatment regimens, in order to improve clinical outcomes.

People experiencing two or more exacerbations of COPD per year are regarded as having frequent exacerbations (Hurst 2010); people who experienced frequent exacerbations in the past often have a progressive decline in lung function and a poorer prognosis (Seemungal 1998). The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study has shown that the strongest predictor of frequent COPD exacerbations in the future is the number of exacerbations experienced in the previous year (Hurst 2010).

In addition, people with frequent exacerbations tend to be more susceptible to viral infections (Wedzicha 2013). In other words, a management strategy that includes virus infection as a treatment target may be effective for people who repeatedly experience COPD exacerbations. Furthermore, some studies suggest that GERD, a disease comprising symptoms, end‐organ effects and complications related to the reflux of gastric contents into the oesophagus, oral cavity or the lung (Katz 2013), is an independent predictor of frequent COPD exacerbations (Hurst 2010; Ingebrigtsen 2015; Martinez 2014; Terada 2008). It is worth highlighting that the relative risk (RR) of an exacerbation over two years in people with COPD and GERD is 1.93 (95% confidence interval (CI): 1.32 to 2.84), i.e. the risk of exacerbation is almost twice as high for people who have GERD (Terada 2008).

As a common condition, the diagnosis of GERD is often made by general practitioners and gastroenterologists in outpatients departments (Shaheen 2006). Prevalence of GERD is rising worldwide, and the associated disease burden is also increasing (El‐Serag 2014). For instance, cumulative incidence of pneumonia has been reported to be significantly higher in people with GERD than in people without GERD (Hsu 2017). Microaspiration of gastric acid tends to occur in people with GERD, and it has been suggested that this condition is pathologically connected to the development of lung diseases (Morehead 2009). Hsu 2017 reported that the use of proton pump inhibitors (PPIs), a pharmacological treatment for GERD, for more than four months increased the risk of pneumonia in people with GERD. A potential explanation of the relationship between PPI and pneumonia is that an increase in pH due to gastric acid suppression might promote bacterial colonization in the oral cavity, which subsequently leads to pneumonia (Gulmez 2007). However, the precise mechanism of the development of pneumonia when using PPIs is still unclear.

The cause of GERD is complex, but there are several known factors. First, gastric reflux occurs when the gradient of pressure between the stomach and the lower oesophageal sphincter is lost, due to low or absent lower oesophageal sphincter pressure and anatomic disruptions of the oesophagogastric junction, such as hiatal hernia (Orlando 2001). Second, oesophageal peristaltic dysfunction (dysfunction of oesophageal contraction movement which eliminates oesophageal contents to the stomach) and prolonged oesophageal acid clearance (a dysfunction of eliminating contents in the oesophagus by the oesophageal contraction movement, secretions from the oesophagus glands or swallowed saliva) can feature in gastroesophageal reflux (Kahrilas 1988; Sugiura 2001). Amongst people with COPD who smoke, nicotine might lead to changes in lower oesophageal sphincter pressure and abnormal oesophageal peristalsis (Pandolfino 2000). Third, certain pharmacological therapies for COPD, including theophylline, beta₂‐agonists, anticholinergics, and corticosteroids, may alter oesophageal sphincter tone and respiratory mechanics, leading to worsened symptoms of GERD (Phulpoto 2005). GERD has been reported to be a frequent comorbidity of COPD, and prevalence of GERD has been found to be higher in people with COPD compared with healthy controls (Casanova 2004; Mokhlesi 2001). Fourth, the prevalence of GERD symptoms tends to be higher in people with severe airway obstruction (Mokhlesi 2001). Lung hyperinflation correlates with COPD severity and requires more inspiratory effort to inhale. This altered mechanism of breathing may increase the transdiaphragmatic pressure gradient on the chest and abdomen, and lead to GERD (Del Grande 2016). Thus, it may also explain the correlation between severe COPD and GERD. Other factors, such as obesity and comorbidities, may also be associated with the increased prevalence of GERD found in people with COPD (Herbella 2010).

The prevalence of GERD in people with COPD has been reported to range from 17% to 78% (Lee 2015). The mechanism underlying GERD that leads to COPD exacerbations is thought to be related to pulmonary microaspiration of gastric acid into airways (Javorkova 2008; Lee 2015), and this mechanism is also thought to be a risk factor for pneumonia (Gaude 2009; Terada 2008). The inflammatory response triggered by GERD may cause the contraction of airways via vagal reflex or further stimulate acid sensitive receptors in the oesophageal wall, both of which may lead to COPD exacerbations (Mansfield 1981; Schan 1994; Tuchman 1984). Furthermore, GERD is considered to be one of the causes of chronic cough, which is a common symptom of COPD (Irwin 2000).

Description of the intervention

PPIs are one of the most effective medications for reducing gastric acid secretion. Since their introduction in the late 1980s, PPIs remain one of the most commonly prescribed medications worldwide (Bashford 1998). Currently, seven PPIs are available (lansoprazole, omeprazole, pantoprazole, rabeprazole, esomeprazole, dexlansoprazole, and vonoprazan), and some are available as over‐the‐counter medications. Vonoprazan is a novel PPI and has been licensed for use to treat GERD in Japan since 2015. In the USA, for example, lansoprazole, omeprazole and esomeprazole do not require prescription, and omeprazole can be purchased in high‐street supermarkets. However, pantoprazole, rabeprazole, and dexlansoprazole are all prescription‐only medications (Chen 2019). In Japan, all PPIs require a prescription. Therefore, consumer usage of PPIs varies from country to country. Nevertheless, PPIs are one of the most prescribed and most consumed medications worldwide.

The family of PPIs has dramatically improved many conditions, such as peptic ulcer disease, as well as being used in the treatment and prevention of gastroduodenal ulcers associated with the use of non‐steroidal anti‐inflammatory drugs (NSAIDs) (Agrawal 2000; Rostom 2002). They are also included in regimens that aim to eradicate Helicobacter pylori (Hu 2017). In the longer‐term, PPIs can prevent pulmonary microaspiration of gastric contents by reducing the production of stomach acid (Lee 2015). PPIs also promote the healing of oesophageal erosion produced by the reflux of gastric acid into the oesophagus (Dekel 2004).

Treatment with PPIs remains the mainstay approach to the management of GERD (Freedberg 2017; Katz 2013). Given that GERD is an independent risk factor for frequent exacerbations of COPD (Hurst 2010), Baumeler 2016 hypothesised that administration of PPIs for GERD might improve the symptoms and frequency of acute exacerbations of COPD. However, this study eventually showed that annual COPD exacerbation rates and severity were higher amongst participants in the PPI group than in those participants who were not receiving PPI. Moreover, in the PPI group, the incidence rates of hypertension, heart failure, diabetes mellitus and dementia were higher and the quality of life was lower than in the non‐PPI group (Baumeler 2016).

The following reasons might partly explain why the effects of PPI on COPD are different from Baumeler's hypothesis that PPI might reduce COPD exacerbations (Baumeler 2016); (1) the effect of PPIs on bacterial infection; (2) the influence of confounding factors; and (3) other effects of PPIs.

First, as gastric acid secretion plays a protective role against infectious agents, prolonged PPI‐induced low acid status can increase the risk of bacterial overgrowth in the stomach and oesophagus (Eom 2011). This bacterial overgrowth caused by long‐term PPI use may heighten the risk of bacterial aspiration (Gaude 2009). It may also be associated with an increased risk of community‐acquired pneumonia (CAP) (Laheij 2004). CAP is a type of pneumonia caused by organisms found regularly outside of hospital settings, such as Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma, as opposed to hospital‐acquired pneumonia (Metlay 2019).

Observational studies have shown a positive association between PPI usage and CAP (Gulmez 2007; Laheij 2004). In a large‐scale population‐based cohort study derived from the Clinical Practice Research Datalink, Braeken 2017 indicated that people with COPD were at a four‐hold increased risk of developing CAP (hazard ratio 4.51, 95% confidence interval (CI): 4.27 to 4.77).

Several meta‐analyses have suggested that short duration of PPI usage, particularly within the first month, may associated with an increased risk of CAP (Giuliano 2012; Johnstone 2010; Lambert 2015). However, it is not yet clear why short‐duration usage of PPIs correlates with increased risk of CAP. In addition, people with COPD and CAP were found to have longer hospital stays and mortality rates when compared to people with CAP alone (Braeken 2015). Thus, it is likely that the increased risk of CAP associated with PPI treatment could eventually lead to further COPD exacerbations.

Second, there are few intervention studies on this topic, and association of confounding factors may be unclear and controversial. As stated previously, studies have suggested that PPI usage may increase the risk of CAP (Gulmez 2007; Laheij 2004). By contrast, other studies have suggested that this associated risk may be due to significant unmeasured confounding (e.g. comorbidities and baseline characteristics) (Jena 2013; Othman 2016). Othman 2016 examined 160,000 new PPI users to investigate whether there was a change in the risk of CAP before and after the prescription of PPIs. This cohort study initially showed that the risk of CAP was higher in those prescribed PPI (RR 1.67, 95% CI 1.55 to 1.79). However, after adjustment for confounding factors, PPI use was associated with a lower risk of CAP (RR 0.91, 95% CI 0.83 to 0.99). Thus, the association between PPI usage and risk of CAP may be due to confounding factors.

Third, PPI may have effects other than acid suppression. Meijvis 2011 suggested that PPIs may not increase either the gastrointestinal or oropharyngeal bacteria that cause CAP (Meijvis 2011). One possible explanation for COPD exacerbation, besides bacterial infections, could be the effects of PPIs on viral infections.

As well as bacterial infections, several viruses (such as the human rhinovirus) have been reported to be associated with exacerbations of COPD (Falsey 2006; Hurst 2005). In previous studies, causes of COPD exacerbations were shown to be mostly bacterial infections, and viral infections were considered to be the cause of only 14% to 18% of COPD exacerbations (Buscho 1978; Smith 1980). However, with the widespread use of pneumococcal vaccines worldwide, the general microbial pathogenesis pathway is likely to have changed and as such, awareness of virus infections in the prognosis of people with COPD is increasing (Metlay 2019). Virus detection during COPD exacerbation has been found to vary from 22% to 60% (Gunawardana 2014; Sethi 2008). Rhinoviruses are the most reported virus in many studies, with influenza and respiratory syncytial viruses also commonly detected. Other existing data also support a causal link between viral infections and exacerbations of COPD (Beasley 2012; Quint 2010; Wedzicha 2013). Sasaki 2009 suggested a possible preventive effect of PPIs against viral infection, and an association with a reduction in COPD exacerbations. This inhibitory effect of PPIs on viral infection could not explain why Baumeler's hypothesis was not completely supported. The efficacy and safety of PPIs in relation to viral infection is still unclear.

Therefore, the effects of PPIs on acute exacerbations of COPD are not yet clear and remain controversial (Filion 2014).

How the intervention might work

It has been suggested that GERD could be an independent risk factor of COPD exacerbation (Hurst 2010). The acid suppression effects of PPIs might play a role in COPD management based on the following mechanisms. Gastric acid secretion is a complex process regulated by at least three types of receptors on the parietal cells (histamine, gastrin, and acetylcholine). Usually, PPIs reduce gastric acid production by irreversibly blocking the enzymes responsible for hydrogen potassium ATPase (proton pump) in parietal cells (Akazawa 2016; Scott 2015). However, vonoprazan has a somewhat unique action, which involves reversibly blocking hydrogen potassium ATPase through competing with potassium ions (Hunt 2015). Thus, vonoprazan is a faster‐acting acid suppressive agent than conventional PPIs. Although vonoprazan differs somewhat from the existing PPIs, it is still classified as a PPI because it inhibits the proton pump and suppresses gastric acid production. PPIs, including vonoprazan, make it possible to reduce gastric acid secretion and to prevent central reflex and pulmonary microaspiration of stomach acid (Lee 2015). However, PPIs can cause gastric and oesophagus bacterial overgrowth by excessive acid suppression (Eom 2011), and may lead to COPD exacerbation (Giuliano 2012; Laheij 2004; Lambert 2015). The same safety concerns have also been discussed regarding vonoprazan (Sugano 2018). In addition, excessive suppression of gastric acid increases the likelihood of developing CAP (Gulmez 2007; Laheij 2004), which may lead to worsening of COPD. Therefore, the relationship between the acid suppression effects of PPIs and COPD exacerbations remains controversial.

In addition to acid suppression, PPIs have been reported to have an impact on viral infections, for example rhinovirus infections (Long 2015; Sasaki 2005). Rhinoviruses are commonly identified viruses in people who experience frequent COPD exacerbations (Hurst 2005). A rhinovirus can amplify the expression of intercellular adhesion molecule‐1 (ICAM‐1) and cytokine (Yu 2017). ICAM‐1 is the major rhinovirus infection receptor and increases viral susceptibility on respiratory epithelial cells (George 2014). Lansoprazole and omeprazole have been reported to have suppressing effects on the expression of ICAM‐1 (Ohara 1999; Watanabe 2001). Researchers found that both lansoprazole and omeprazole were able to suppress viral infections by inhibiting vacuolar hydrogen potassium ATPase, thereby increasing endosomal pH and inhibiting the expression of ICAM‐1 (Sasaki 2005). Other studies have also suggested that PPIs may possess systemic anti‐inflammatory effects (Becker 2006; Sasaki 2011). Viral infections induce inflammatory mediators, including various cytokines (Sethi 2008). The anti‐inflammatory effect of PPIs is probably due to their effect of inhibiting the production of proinflammatory cytokines (Sasaki 2011). However, these antiviral and anti‐inflammatory effects of PPIs are primarily in vitro observations. Thus, evidence based on human studies is currently lacking. People who experience frequent COPD exacerbations may have a high sensitivity towards respiratory viral infections or have poor ability to prevent viral replications (George 2014), which makes PPIs a viable treatment option for COPD.

Why it is important to do this review

COPD exacerbations are associated with substantial impact at both the individual level and for overall society (Barnes 2013; Wedzicha 2013). Therefore, effective management of existing COPD symptoms and prevention of exacerbations is a major therapeutic target. Given that the frequent‐exacerbation phenotype of COPD is known to be associated with a history of gastroesophageal reflux or heartburn (Hurst 2010), PPIs may have the potential to influence COPD exacerbations. Since PPIs are widely available, with millions of users worldwide, it is necessary to evaluate the role of PPIs on people with COPD in this context.

We have identified a randomised controlled trial (RCT) (Sasaki 2009), and some other studies on this topic. To our knowledge, there is no existing systematic review that explores the precise role of PPIs in the management of COPD, so this remains to be ascertained. Therefore, a systematic review is necessary to determine whether PPIs are useful to treat people with COPD.