Discussion
We performed a survey on bacterial infections in one of the largest cohorts of patients with type 1 diabetes in the world. By combining data from two different nationwide registries that are mandatorily used in Finland, we were able to study the incidence of infections causing hospitalization as well as infections treated in the outpatient setting. Owing to the large number of patients and follow-up years, we were also able to study the association between bacterial infections and diabetic nephropathy. We observed that bacterial infections were more common in patients with type 1 diabetes compared with age-matched and sex-matched NDC subjects, and that the incidence of bacterial infections increased in parallel with the severity of diabetic nephropathy. The use of antibiotics also correlated with the long-term glycemic control in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria. Frequent bacterial infections and recurrent use of antibiotics were also associated with an increased risk of incident microalbuminuria in patients with diabetes.
Previous studies have shown that patients with diabetes are at higher risk of hospitalization due to bacterial infections.13 ,22 On the basis of our hospital discharge register data, we observed that the risk of hospitalization due to bacterial infections was 4.3-fold higher in patients with type 1 diabetes, compared with NDCs. Our results also indicate that type 1 diabetes was associated with an increased risk of less severe infections, treated outside of hospitals. The overall number of annual antibiotic purchases was, on average, twofold higher in patients with diabetes than in control subjects. This difference might partly be explained by the general awareness of risks of infections related to diabetes itself, and it is possible that the threshold for clinicians to prescribe antimicrobial medications is lower, and the antibiotics may be prescribed in a prophylactic manner for patients with diabetes.
Albuminuria and reduced GFR have previously been associated with an increased risk of infection-related mortality.17 ,18 We observed that diabetic nephropathy at all stages was a risk factor for bacterial infections. Microalbuminuria did not increase the rate of hospitalization due to bacterial infections, but macroalbuminuria doubled the rate compared with patients with normal AER. Similar findings were found in the corresponding results for outpatient antibiotic purchases, where microalbuminuria increased the number of annual antibiotic purchases by 1.2 times and macroalbuminuria by 1.3 times. ESRD has previously been shown to be a strong risk factor for infectious diseases,16 and in our study dialysis increased the rate of hospital-treated bacterial infections by 11 times and the number of annual antibiotic purchases by 2.4 times compared to patients with diabetes and normal AER. Since long duration of diabetes increases the risk of diabetic complications, an important question that arose was how the duration of diabetes influenced the incidence of bacterial infections in patients with diabetes. We found that each year of the duration of diabetes increased the number of antibiotic purchases by 2.6%. However, when adjusting for the nephropathy status, the increase was 1.4%. Patients with incident microalbuminuria purchased significantly more antibiotics at the time of microalbuminuria diagnosis, compared with 4 years before the progression. These observations could suggest that bacterial infections may be associated with the development of diabetic nephropathy.
Hyperglycemia has been shown to cause immunosuppression, and to increase the susceptibility to bacterial infections.7–9 ,23 Several studies have demonstrated that poor glycemic control is a considerable risk factor for infections in patients with diabetes.1 ,10 ,24 Although hyperglycemia could be a promoting factor for bacterial infections, infections themselves may also cause hyperglycemia.25 Hence, a vicious cycle may arise as frequent infections can worsen the glycemic control in patients with diabetes, and conversely, chronic hyperglycemia may facilitate the development of infections.26 We observed that poor glycemic control correlated with the number of antibiotic purchases, and that the relationship did not differ between the various nephropathy groups. The number of antibiotic purchases increased by 6–10% for each unit increase in HbA1c at all stages of nephropathy. As chronic hyperglycemia remains the primary cause of metabolic, biochemical, and vascular abnormalities in diabetic nephropathy, it could be argued that poor glycemic control may be the link between the progression of diabetic nephropathy and the higher incidence of bacterial infections.
Some limitations must be considered in our study. Data from the National Drug Prescription Register do not reveal the type or site of the infection for which the antibiotic treatment was required, only the compound itself, and the number of packages sold are recorded in the register. Based on the reports from the Finnish Medicines Agency,27 hospitals annually purchase about 15–20% of all antimicrobial drug purchases in Finland, and these purchases are not recorded in the National Drug Prescription Register. Of note, most of these infection events are recorded in The Hospital Discharge Register, and included in our study as infections that led to hospitalizations. The Hospital Discharge Register also has its own drawbacks. Owing to limitations of the ICD-coding system, it can sometimes be challenging to retrospectively establish the specific etiology of the infections—whether they are viral or bacterial in origin. It should be noted that certain types of infections are much more often encountered in patients with diabetes than in patients without diabetes; for example, patients with diabetic neuropathy are prone to foot ulcers, which when infected can lead to osteomyelitis and possibly even bacteremia. Also, physicians often have a lower threshold for admitting patients with diabetes into hospital care due to an infection, compared to patients with an infection without any underlying disorders. This contributes to the large difference in the number of hospitalizations seen in patients with diabetes when compared with the NDC subjects.
Our study shows that bacterial infections are more frequent in patients with type 1 diabetes compared with age-matched and sex-matched NDCs, both in hospital and outpatient settings. Although our study cannot ascertain whether bacterial infections lead to the development and progression of diabetic nephropathy, or if the nephropathy predisposes the patient to bacterial infections, it does show that there is a strong association between the two. Bacterial infections could cause kidney injury via endotoxins,28 ,29 or by direct invasion of pathogens, which may lead to inflammation and renal scarring. Chronic hyperglycemia could also predispose to infections as well as the progression of nephropathy. More studies are required to elucidate which risk factors increase the susceptibility to bacterial infections in patients with type 1 diabetes, and to further investigate the association between bacterial infections and the risk of the development and progression of diabetic nephropathy.