In this population-based study of 15,000 COPD patients, we show that individuals discharged with a COPD diagnosis have a 2.5-fold increased incidence of invasive disease from a wide range of bacterial pathogens compared to the general population, independently of socio-economic status and co-morbidities at base-line.
We hypothesized an increased incidence of invasive diseases caused by bacteria associated with colonisation of the airways in COPD, due to impaired barrier functions. But increased incidence was also observed for other major pathogens normally associated with non-respiratory infections, i.e., Staphylococcus aureus and enterobacteriaceae, indicating a general susceptibility to invasive infections of non-respiratory origin, which in turn could be due to different mediating factors.
COPD is currently recognised as a disease with systemic manifestations not limited to airflow obstruction and is associated with several serious co-morbidities . It is therefore plausible to believe that COPD also confers increased incidence of invasive bacterial infections of non-respiratory origin. In contrast to our results, a Danish study concluded that underlying COPD did not predict hospitalizations due to infections outside the respiratory system . The study was based on 2,200 individuals with COPD who were subdivided into GOLD classes according to FEV1. Re-examining the incidence rates in the Danish study does suggest an increased risk of hospitalisation for non-respiratory infectious diseases for COPD as a group, although there was no clear trend of increased risk with increasing GOLD stage. This classification, based solely on FEV1, may not be sufficient to capture the full effect of co-morbidities in COPD .
The increased incidence of infection in COPD could also, to some extent, be mediated by the use of corticosteroids, anticholinergic inhalants or smoking. A limitation of the present study is the lack of individual information on COPD severity, corticosteroid use or smoking status which is not available in the national databases.
The use of corticosteroids is an indisputable risk factor for infection. However, risk estimates from observational studies are limited by confounding by indication and the nature of the underlying disease is an important modifier of the infection risk, making it difficult to generalise results from different disease groups . In a pooled analysis of 71 controlled clinical trials, a relative risk of 1.6 for infectious complications were reported in patients given more than a cumulative dose of >700 mg prednisone , but a stratified analysis of trials including patients with pulmonary diseases showed no increased risk of infectious complications . Neither Smyllie et al. (case–control study of 500 patients with respiratory diseases)  nor Niewoehner et al. (randomised controlled trial of oral steroid treatment for two or eight weeks in COPD), found statistical significant differences in secondary infections . In contrast, some meta-analyses of randomised control trials have reported that treatment with inhaled corticosteroids is associated with a 50-70% increased risk of pneumonia [15, 16]. However, no increased risk was reported in pooled analyses of trials using budesonide . A side-effects of anticholinergic agents is urinary retention, which can predispose to urinary tract infections. Barr et al. (systematic meta-analysis of 3 clinical trials) report an OR of 1.6 for urinary tract infections in users of tiotropium vs. placebo .
Smokers have an increased risk of infectious complications but it is has not been shown that smoking is a risk factor for bacteraemia not mediated through bacterial colonization of the airways [19, 20]. The comparisons in the present study are not made between a smoking and a non-smoking group; population-based studies of COPD in Sweden have reported current smoking rates from 47% (in 1992) to 34% (in 2004) in COPD patients compared to 33% and 13%, respectively, in non-COPD subjects in these studies [21, 22]. A survey of COPD patients in secondary care (2007) showed that 23% were still smokers  compared to national estimates of around 16% (2005) in the adult population (>45 years of age) .
Register-based studies from national databases have several advantages but also important limitations. The study design, using a reference population that is randomly drawn from the background population and standardised for age, gender, county, allows adjustments for co-morbidity confounders, which is not possible in designs based on national estimates, producing SIRs (standardised incidence ratios).
The study covers all patients hospitalised with COPD in Skåne during the observation period, but individuals with COPD treated only as outpatients were not included in the analysis. However, we found no effect modification by the level of COPD diagnosis; thus risk estimates were similar in subjects identified with COPD as main diagnosis (hospitalised because of COPD) and as an additional one (hospitalised with COPD). The prevalence of physician-diagnosed COPD in Sweden is estimated to be 5-10%, and in our study, 7.2% of the randomly selected general population control subjects had a hospital discharge diagnosis of COPD during the observation period. This result implies that a large proportion of patients with COPD will eventually be hospitalised either because or with COPD.
General validation studies of the Swedish Inpatient Registry indicate that the coverage is above 98% and that almost 90% of the reported diagnoses are correct [25–27]. We have previously validated the COPD in this registry . The amount of evidence supporting the diagnosis varied, but less than 10% were considered to be misclassified or having an uncertain COPD diagnosis. All stages of COPD-severity were seen since patients were admitted due to a number of reasons, not necessarily linked to COPD, but the degree of validity did not differ between COPD as a main or additional diagnosis. A misclassification of the COPD-diagnosis in the present study, in addition to the inclusion of COPD patients receiving only outpatient care as control subjects, would presumably bias the estimates downwards.
Diagnoses of infectious diseases from the Swedish Inpatient Registry have not been validated separately, except for infections in intensive care (CNS-infections, pneumonia and sepsis) with the overall pattern of varying sensitivity (38-99%) but high specificity (98.6-99.6%) . The misclassification of clinical diagnosis are assumed to be non-differential except for pneumonia, which could theoretically be prone to increased misclassification in COPD patients due to the sometimes diagnostic dilemma to differ between episodes of exacerbation, heart failure or pneumonia .
We adjusted our models for the use of inpatient care at baseline and inpatient co-morbid conditions associated with COPD and conferring increased risk of infection. Residual confounding from co-morbid conditions requiring only outpatient care cannot be ruled out.
In Sweden, there is as general recommendation to perform blood culture (at least) before treating patients with intravenous antibiotics. Whether the adherence to these guidelines is greater or less for COPD patients than for individuals without COPD is not known. In the present study the, hazard ratios were similar when using an in-patient control group, indicating that the risk of ascertainment bias is limited.
We conducted a population-based cohort study of the incidence of severe bacterial infections in COPD patients spanning 20 years covering all residents of the County of Skåne, an area with approximately 1.2 million inhabitants. We believe that the results are generalizable to many settings, although differences in population composition or access to health care are likely to influence the results.