Articles indexed within Ovid MEDLINE were searched between 1995 and May 29, 2014, using both medical subject heading and key search terms alone and in combination. Search terms used included diabetes mellitus, diabetes, infection(s), communicable diseases, cohort, case-control prospective, longitudinal, retrospective, follow-up, epidemiology, or public health. The search strategy was strengthened by inclusion of an additional citation search on one key article from the Netherlands which has
ReviewDiabetes and infection: assessing the association with glycaemic control in population-based studies
Introduction
Diabetes is one of the leading causes of morbidity worldwide, and creates a huge burden of disease. Diabetes is associated with a range of severe acute and chronic complications, which results in a correspondingly large financial burden. It has been estimated that US$612 billion are spent annually on diabetes care, accounting for 11% of total adult health spending.1 In high-income countries, diabetes prevalence increases steeply with age,2 and more than 25% of older adults (throughout this Review older people refers to those aged 70 years or older) in British care homes might have diabetes.3
A relation between diabetes and infection has long been accepted clinically. Some rare infections, known as signal infections4, 5 (severe infections which are not self-limiting and are likely to be diagnosed irrespective of differences in physician behaviour or previous diagnosis of diabetes), are often pathognomonic of a patient having diabetes (panel 14, 5, 6).7, 8 Examples of signal infections include emphysematous pyelonephritis, malignant otitis externa,9 mucormycosis,10 and Fournier's gangrene.8 Although other infections, such as lower respiratory tract infections, urinary tract infections, and cellulitis, are very common in the general population, people with diabetes are at higher risk.6 A key primary care study in the Netherlands6 prospectively followed up 7000 patients with diabetes for 1 year, comparing their attendances for infection with those of control patients with hypertension. Results of this investigation reported that patients with type 1 diabetes and type 2 diabetes were at high risk of lower (but not upper) respiratory tract infections (type 1 diabetes: adjusted odds ratio [aOR] 1·42 [95% CI 0·96–2·08], type 2 diabetes: 1·32 [95% CI 1·13–1·53]), and urinary tract infections (type 1 diabetes: aOR 1·96 [95% CI 1·49–2·58], type 2 diabetes: 1·24 [95% CI 1·10–1·39]). A study11 in the USA estimated that 10% of Emergency Department visits in patients with diabetes resulted from infection, and patients with diabetes were twice as likely to be admitted to hospital with infection as were patients without diabetes. Results of a population-based study12 from Canada reported that almost half of the patients with diabetes had an infection that led to hospital admission or a physician insurance claim over a 1 year period.
Infections can be particularly common and more serious in older people with type 2 diabetes.13 The rise in diabetes prevalence is most alarming in older people in high-income countries, and an analysis14 of primary care data in the UK in older patients with diabetes noted that the burden of diabetes-associated infections rose by 30% between 1997 and 2010, with lower respiratory tract infection having the highest incidence (152·7/1000 person-years). This substantial increase was attributed to both the rising prevalence of type 2 diabetes, and population ageing.15 Furthermore, evidence suggests that diabetes care and targets are often neglected in older people.2, 16 The 2015 draft NICE guidance for type 2 diabetes17 did not include any management or prevention strategy for infection, nor did a position statement on diabetes in older people.18
Evidence from a meta-epidemiological review19 of 97 prospective cohort studies (820 900 people with diabetes) that assessed the risk of cause-specific mortality reported a substantial increased risk of infection-related mortality when excluding pneumonia (relative risk [RR] 2·39, 95% CI 1·95–2·93; 1083 deaths) and of pneumonia mortality itself (RR 1·65, 95% CI 1·45–1·92).19 Results showed an increased risk for death from all causes in patients with diabetes, compared with people without diabetes (RR 1·80, 95% CI 1·71–1·90). This high all-cause mortality risk is not supported by the higher quality evidence from randomised controlled trials, but this might be because these epidemiological studies included older patients, and more patients with comorbidities or diabetes complications, who are frequently excluded from the randomised controlled trials. Panel 2 outlines in more detail the relation between diabetes and infections in older people.
Randomised controlled trials have suggested microvascular and macrovascular benefits from improved glycaemic control in younger, fitter people.26, 27, 28 Randomised controlled trials29, 30, 31 that included older patients (over 60 years), with a longer history of diabetes and at higher cardiovascular risk, did not find convincing evidence of any benefits on all-cause cardiovascular disease mortality.20 Reviews and editorials on this topic have concluded that “further assessment of the risks and benefits (of tight glucose control) [in all people with diabetes] is therefore needed”.20, 32 Trial evidence thus far has led to well documented and accepted targets for glycaemic control, and national guidelines for prevention of complications in people with diabetes.17 For example, the NICE guidelines17 for glycaemic control focus on macrovascular and microvascular outcomes, and do not mention the potential association between glycaemic control and infection.
Infectious disease risks have been neglected, and have not been reported by most of these trials, despite immunological evidence (panel 3) that hyperglycaemic states negatively affect outcomes during infections in patients with diabetes.33, 34, 35 Patients with diabetes are not only more susceptible to infection but often have different disease courses once the infection has been established, which is reflected by increased rates of hospital admission,43 length of stay,44, 45 and complications.46 Therefore, infections in older patients with diabetes could have at least as much effect on their quality of life as macrovascular and microvascular risks.
Other review articles7, 51, 52 have considered the association between diabetes and infection, but none have presented a comprehensive review of the effects of glycaemic control on infectious disease outcomes. In this Review, we examine the mainly observational evidence from population-based epidemiological studies that assess the association between infection risk and glycaemic control in type 1 and type 2 diabetes, and the potential effect of ageing on this association.
Section snippets
Association of glycaemic control with infection susceptibility and outcomes
We identified 13 population-based studies that met our inclusion criteria (table). We treated the case-control and cohort study from the same Health Maintenance Organization54, 55 as separate studies but describe their results together. Nine studies were longitudinal in design and three were case-control studies. We identified one randomised controlled trial that reported on infection outcomes as part of monitoring for adverse events. In this Review, we qualitatively summarise the studies and
Randomised controlled trial evidence of intensive glycaemic control
One of the early landmark randomised controlled trials, the Diabetes Control and Complications Trial (DCCT),21 reported infection outcomes, albeit in a very specific population (1441 people aged 13–39 years on study entry, all with type 1 diabetes). Trial participants were randomised to receive intensive therapy or conventional therapy (control group) and were prospectively followed up for infections every 3 months. Infections were common—eg, 5·6 foot infections were recorded per 100
Longitudinal (cohort) studies
An early prospective cohort study53 in general practice in the Netherlands followed up 328 people with type 2 diabetes for 2 years, measuring HbA1c every 3 months for a total of eight occasions. 458 infections were identified; most infections were either urinary tract infections, upper respiratory tract infections, or fungal infections. The mean HbA1c was slightly higher in patients with infections, compared with those without, and this result was of borderline statistical significance (mean HbA
Population-based case-control studies
Several very large Danish population-based case-control studies60, 63 looked at specific infections in whole communities. One study60 recruited around 350 000 participants in total between 1997 and 2005 (34 239 cases of pneumonia and 342 390 controls matched for age and sex) to assess the risk of first time hospital admission for pneumonia in patients with diabetes. This study adjusted for key confounders such as age, sex, comorbidity, alcohol-related disorders, use of immunosuppressants,
Cohort and case-control study based in the same population
Boyko and colleagues carried out a case-control study54 and then a prospective cohort study55 using administrative data from a Health Maintenance Organization in Washington, USA. The case-control study reported no association between infection and glycaemic control, but HbA1c was measured in only 159 women aged 55–75 years with diabetes, and measurements were made using three different glycated haemoglobin assays, before standardisation of HbA1c measurements was strengthened.53 In the
Method issues and limitations of existing research
The only randomised controlled trial included, DCCT,20 recruited young adults and adolescents (aged 13–39 years at study entry) with type 1 diabetes, and infection was a secondary outcome. With the exception of DCCT, the studies included were observational, identifying associations but not clearly showing causality. We included only larger, population-based observational studies in this Review, excluding many hospital-based cohorts, which often lack external validity. Most of the studies
Conclusion
The association between the high HbA1c concentrations described in this Review and a 2–4 times higher risk of infection have been reported from large and well designed population-based studies, mainly from the USA, UK, or Scandinavia. Results from one trial, DCCT,21 noted a reduction of about 40% in the rate of some key common infections for those randomly assigned to more intensive diabetes management. The epidemiological data show a strong link between diabetes and the development of
Search strategy and selection criteria
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