| | Macro and microvascular complications are determinants of increased infection-related mortality in Brazilian type 2 diabetes mellitus patientsReceived 20 April 2006; accepted 20 April 2006. published online 24 May 2006. Abstract ObjectiveTo investigate infection-related mortality and its predictors in Brazilian type 2 diabetic patients. MethodsIt was carried out a long-term prospective study with 471 type 2 diabetic outpatients. Several clinical, laboratory and electrocardiographic variables were recorded at baseline. Predictive factors for infection-related mortality were evaluated by Kaplan-Meyer estimation of survival curves, univariate and multivariate Cox survival analysis. Excess infection-related mortality in this cohort was evaluated by comparing its rate with that of the Rio de Janeiro background population and calculating standardized mortality rates (SMR). ResultsDuring a median follow up of 57 months (range: 1–86 months), 40 (33.1%) patients died from infection-related causes. After adjusting for age and sex, the infection-related SMR was 6.6 (95% confidence interval [95% CI]: 4.8–9.0). In Cox multivariate analysis the predictors of infection-related mortality were older age (hazard ratio [HR]: 1.91; 95% CI: 1.35–2.70), pre-existing peripheral arterial disease (HR: 3.86; 95% CI: 1.80–8.28) and cerebrovascular disease (HR: 3.28; 95% CI: 1.24–8.70), lower HDL-cholesterol (HR: 2.50; 95% CI: 1.32–4.74) and increased 24 h-proteinuria (HR: 1.22; 95% CI: 1.08–1.37). After excluding patients with peripheral and cerebrovascular disease at baseline, neuropathy and coronary heart disease were selected as predictors of mortality, besides older age and proteinuria. ConclusionsBrazilian type 2 diabetic patients have a six-fold excess infection-related mortality than the general population. This increased mortality is mainly determined by the presence of micro and macrovascular complications. Multifactorial risk interventions are needed in order to decrease this burden of infection-related mortality. 1. Introduction  Patients with type 2 diabetes have increased all cause-mortality when compared to non-diabetic patients, mainly due to cardiovascular causes [1], [2], [3], [4]. The development of micro and macrovascular complications, the occurrence of end-stage renal disease and cardiovascular disease are the major contributors to the excess mortality in type 2 diabetes. Nonetheless, there is a variable effect of diabetes on all causes of death between countries [1]. Reporting data from different countries permits to identify which causes of death are increased in individuals with diabetes and to observe any differences in the pattern of mortality [1]. Diabetes is widely believed to predispose to infections. However, there is no strong epidemiological evidence linking diabetes and serious infections [5], [6]. Diabetic patients have higher case-fatality rates from infections [7], [8], probably not only due to altered host defenses but also to increased presence of underlying disorders that predispose to mortality. The effects of neuropathy and impaired tissue perfusion on injury and wound healing are also among the conditions that may increase infection-related morbidity and mortality [9]. The risk of infection-related mortality was remarkably increased in American type 2 diabetic adults compared with those without diabetes but, apparently, only in those diabetic patients with congestive heart failure [6]. We have recently reported in a cohort of Brazilian type 2 diabetic patients that global and cardiovascular mortality rates were three times greater than the background population [10]. In this cohort, infection was the second most frequent cause of death, quite close to cardiovascular diseases [10], [11]. Information regarding the risks of mortality related to infection is not available in Brazilian type 2 diabetic patients. In this context, we planned to study in this population the burden of diabetes on infection-related mortality when compared with the background population and also to investigate the potential predictors of infection-related mortality. 2. Patients and methods 2.1. Study subjects and baseline procedures Characteristics of the study patients have been previously described [11], [12]. Briefly, all adult diabetic outpatients according to the 1985 WHO criteria who had standard ECGs recorded from July 1994 to June 1996 were consecutively enrolled in this study. After the appliance of clinical and electrocardiographic exclusion criteria detailed elsewhere [11], [12] a total of 471 type 2 diabetic patients made up the cohort. Local ethics committee approved this protocol and all the patients gave signed informed consent. The baseline procedures and criteria for diagnosing clinical variables have also been described [11], [12]. All the patients were submitted to a complete clinical examination, with particular attention to signs and symptoms of cardiovascular diseases and diabetic degenerative complications. In summary, coronary heart disease was diagnosed by clinical and electrocardiographic criteria (Minnesota codes [13]: 1.1–1.3, 4.1–4.4 and 5.1–5.3); heart failure was based on Framingham criteria [14]; and cerebral or peripheral vascular disease by history and physical examination. Diabetic retinopathy was evaluated by an ophthalmologist; clinical nephropathy needed at least three proteinurias ≥0.5mg/24h or confirmed reduction in glomerular filtration rate (creatinine clearance <1ml/s or serum creatinine >130μmol/l); and peripheral neuropathy by clinical examination. Mean values of all office systolic (SBP) and diastolic (DBP) blood pressures measurements performed during the first year of follow-up were obtained. Arterial hypertension was diagnosed if mean SBP ≥140mmHg or DBP ≥90mmHg or if anti-hypertensive drugs had been prescribed. Laboratory evaluation included fasting plasma glucose, serum fructosamine, creatinine, triglycerides, total and high-density lipoprotein (HDL) cholesterol, and 24h-proteinuria obtained by automated methods. Mean values of all laboratory exams performed during the first year of follow up were recorded (median number of measurements: 3). From standard resting 12-lead ECGs, abnormalities were registered according to the Minnesota code except left ventricular hypertrophy that was verified by voltage criteria, either Sokolow-Lyon (SV1+RV5 or V6≥3.5mV) or Cornell sex-specific (SV3+RaVL≥2.0mV in women or 2.8mV in men). The ECG intervals were measured as previously reported [12] by a single independent observer and maximum heart rate-corrected QT-interval duration (QTcmax) recorded. Forty-five randomly chosen ECGs were analyzed twice with at least 6 months between the measurements in order to assess reproducibility. Intraobserver mean relative error was 1.1% for QTcmax measurement. 2.2. Follow-up and ascertainment of infection-related mortality The patients were evaluated regularly at least two times a year until June 2001. Those that failed to attend to the hospital were contacted annually to determine vital status. Forty-three (9.1%) patients were lost from follow-up and were considered as censored observations at the date of their last hospital visit. The primary endpoint for this report was infection-related mortality. Death during the follow-up period was ascertained from medical records, death certificates and interviews with their attending physicians and families, through a standard questionnaire reviewed by an independent observer. Causes of death were coded according to the International Classification of Diseases (ICD 9th revision was used until December 1995, ICD 10th afterwards). Infection-related mortality was defined as that occurring in up to 10 days during a hospital admission with an infectious disease diagnosis or if an infection-related code was listed as the underlying cause in death certificates. These included ICD 9th codes 001-139; 320, 321, 326; 421; 460–466; 510, 513, 551, 567, 590, 599; 680–686; 711, 730; and ICD 10th A00-99; B00-99; G00-09; I33; J00-22, J85-86; K65; L01-08; M00-01, M86; N39. The same ICD codes were used to estimate infection-related mortality in the general background population of Rio de Janeiro from the General Death Registry data of the city. 2.3. Statistical analysis Statistics were performed using the STATA version 7.0 software. Continuous data were described as means and standard deviations. The comparison of infection-related mortality between this cohort and the population of Rio de Janeiro city (using mid-point 1996 population) was made by calculating the standardized mortality rates (SMRs). The 95% confidence intervals (95% CI) for age and sex-adjusted SMRs were calculated under Poisson assumption. Kaplan-Meyer estimation of mortality curves (compared by log-rank tests) and univariate and multivariate proportional-hazards Cox models were employed for survival analysis. Serum creatinine was log10 transformed due to its positive skewed distribution. Missing data were frequent for 24h-proteinuria (25%) and serum HDL-cholesterol (32%). To delete subjects with a missing value on one predictor variable included in multivariate models commonly leads to biased results and surely to loss of power [15]. So, to decrease bias and increase statistical efficiency, we imputed missing data using the expectation maximization method. Variables with a p-value <0.20 in Cox univariate analysis entered the multivariate models. Different multivariate models were fitted in a forward stepwise strategy for infection-related mortality, first including all diabetic patients then excluding patients with pre-existent cerebrovascular and peripheral vascular disease. Assumptions of the proportional-hazards models and interactions were tested [16] and no violation or significant interaction was observed. Results were presented as hazard rates (HR) with 95% CIs. A two-tailed p-value <0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics and follow-up infection-related deaths After a median follow-up of 57 months (range: 1–86 months), corresponding to 1835.25 patient-years of follow-up, 40 (33.1%) patients died from infection-related causes: 19 (47.5% of them) from a cutaneous site of infection, 17 (42.5%) from pulmonary, 3 (7.5%) from urinary and one (2.5%) from undetermined source of infection. Table 1 shows the baseline characteristics of survivors and deceased patients from infection-related causes. Patients with infection-related deaths were older, had longer duration of diabetes, and had higher prevalence of neuropathy, heart failure, coronary, cerebrovascular and peripheral vascular disease. Also non-survivors had increased serum creatinine, 24h-proteinuria and decreased serum HDL-cholesterol. They had more frequently ECG signs of ischemia or fibrosis, greater prevalence of QTcmax prolongation and a slightly higher heart rate. 3.2. Univariate survival analysis Age, the presence of peripheral arterial disease and cerebrovascular disease at baseline, 24h-proteinuria and serum HDL-cholesterol were the variables with the strongest univariate association with infection-related mortality (Table 1). Kaplan-Meyer estimation of mortality curves for patients grouped according to these variables demonstrated that all were capable of distinguishing subgroups of patients with significantly different infection-related mortalities (Fig. 1). 3.3. Multivariate survival analysis Results of multivariate Cox survival analysis are shown in Table 2. Older age, the presence of peripheral and cerebrovascular disease at baseline, increased 24h-proteinuria and decreased HDL-cholesterol were the predictive factors for infection-related mortality. After excluding patients with pre-existent peripheral and cerebrovascular disease, the presence of peripheral neuropathy and coronary heart disease were selected as predictors of mortality due to infection, besides age and 24h-proteinuria. 3.4. Standardized mortality ratios The crude incident infection-related mortality rate was 21.8 per 1000 patients-years (95% CI: 16.0–29.7). Table 3 shows infection-related SMRs for patients stratified according to sex and age ranges. Type 2 diabetic patients had an overall 6.6-fold (95% CI: 4.8–9.0, p<0.001) excess infection-related mortality adjusted for age and sex than the general population of Rio de Janeiro. The increased mortality was slightly higher in women than in men and more important between the sixth and the eighth decade of life in both sexes. After this age range there were too few patients in the strata to confirm the increased SMRs observed, as shown by the wide 95% confidence intervals, which included unit. 4. Discussion The two main findings of this prospective study with up to 7 years of follow-up are first that Brazilian type 2 diabetic patients have a six-fold excess infection-related mortality compared to the general population. Second, that the presence of macrovascular and microvascular complications, specifically peripheral arterial disease, cerebrovascular disease, coronary heart disease, clinical nephropathy (defined by increased proteinuria) and peripheral neuropathy, are the main determinants of this increased mortality. It is not unexpected that macrovascular and microvascular complications were selected as predictors of increased infection-related mortality. It has been reported that the presence of concurrent cardiovascular disease, particularly heart failure, led to a higher risk of infection-related death, apparently increasing susceptibility to infection or increasing the severity of infection [6]. In this investigation [6], based on the Second National Health and Nutrition Examination Survey (NHANES II) data, the diabetic specific risk of infection-related mortality was independent of the presence of heart failure or heart attack at baseline. Much of this increased risk of infection could probably be explained by the finding that diabetes strongly predisposed infection-related mortality when ischemic heart disease, heart failure or stroke were present at death [6]. In fact, when these deaths were excluded, diabetic patients had the same risk for infection-related mortality as those without diabetes [6]. We found pre-existent cerebrovascular and peripheral arterial disease as independent predictors of infection-related mortality. Different from ours, this study could not analyze the independent association of cerebrovascular and peripheral arterial disease with increased infection-related mortality, because of absence of this information at baseline. In our study, the presence of peripheral vascular disease and/or neuropathy probably increased the risk of cutaneous infection, the most frequent source of infection in our patients, and also, possibly, increased the risk of pulmonary infection due to reduced mobility. The presence of cerebrovascular disease may have increased the risk of pulmonary infection due to decreased airway protection mechanisms and reduced mobility. Not unexpected, low serum HDL-cholesterol, a traditional marker of macrovascular atherosclerotic disease, was also selected as an independent predictor of infection-related mortality. When patients with cerebrovascular and peripheral arterial disease at baseline were excluded from the survival analysis, the presence of pre-existent coronary heart disease and neuropathy were selected as predictors of infection-related deaths, supporting that the presence of these co-morbidities might increase susceptibility to infection or make infection clinical course more severe. Although the diagnostic criteria for coronary disease considered in our study was different from that of Bertoni et al. [6], which used only self-reported history of heart attack; in contrast with their results, we observed a three-fold independent increased risk of dying from infection-related causes in diabetic patients with coronary heart disease at baseline. In agreement with our results, coronary heart disease has been identified as an independent predictor of mortality in patients with community-acquired pneumonia [17]. A strong relationship between diabetes and infection-related mortality has been previously demonstrated in individuals less than 70 years old at baseline [6]. In our study, this relationship persisted until the eighth decade of life, although it was much stronger at younger ages. Although increased 24h-proteinuria is an established marker of increased global and cardiovascular mortality [18], [19], no study has specifically addressed the presence of abnormal proteinuria in diabetic patients as a predictive factor for infection-related mortality, as we found in the present report. Proteinuria, specifically in nephrotic range, is associated with increased susceptibility to infection [20]. With regard to glycemic control, neither fasting glycemia nor serum fructosamine were of prognostic importance to infection-related mortality. As HbA1c values were not available in this study, glycemic control status was not adequately evaluated and our data do not allow conclusions about its prognostic value. The most worrisome finding of our study was a six-fold excess infection-related mortality in comparison to the background general population. No other group reported such high infection-related SMRs. The increased risk was, in general, up to two-fold [4], [6], [21], [22] and, rarely, greater than this [23]. We believe that our figure is probably somewhat overestimated. First because of our pre-definition of infection-related deaths as those occurring in up to 10 days of hospitalization with an infectious disease diagnosis or those with main or underlying infection ICD codes on death certificates. This led to the fact that infections were the second most frequent cause of death (33.1% of all deceased patients), very near to cardiovascular causes (36.3%) [11]. In general, cardiovascular causes of death are much more prevalent in other populations [1], [2], [4], [23], except one report from Thailand [24] where infection was the leading cause of death. Crude infection-related mortality rates in diabetic individuals generally ranged from as low as 5 per 1000 patient-years [4], [6] up to 10 per 1000 patient-years of follow-up [24]. In the present study it was twice (21 per 1000 patient-years) the highest rate reported. Another aspect that should be considered is that our patients made up a tertiary-care hospital-based cohort, so they probably had more severe disease at baseline. Second, infection-related mortality in the background population might also have been underestimated, since only the main underlying cause of death was available in our general registry of deaths. So, deaths with infection as a contributing but not the main cause of death in death certificates were not accounted for in the general population. Also, death certificates have generally low sensitivity for infectious diseases [25] and lower likelihood for an infection disease to be deemed the underlying main cause of death when infection is listed as a cause of death [26]. Moreover, clearly, infection is nowadays an uncommon cause of death because of improvements in supportive care, effective antibiotics and infection control in the past decades. Therefore, the combination of a possibly overestimated infection-related mortality in our cohort with underestimated infection mortality in the background general population could have led to this increased infection-related SMR. On the other hand, clearly, at least part of this markedly enhanced risk of infection-related deaths in Brazilian diabetic patients is due to true differences between populations. It must be recognized that this study had several limitations. Some potentially important prognostic variables, such as HbA1c, previously discussed, anthropometric measures, smoking status and microalbuminuria were unavailable at baseline. Microalbuminuria is an established risk factor for mortality in diabetic patients [19], [27]. Possibly, 24h-proteinuria could have replaced its prognostic information. It has not been shown in smokers an increased risk of mortality in patients with community-acquired pneumonia [7]. And, also, no effect of increased body mass index has been demonstrated in diabetic patients [6]. Thus, we think that the absence of adjustment for smoking status and anthropometric measures probably did not influence the strength of the association between the variables and infection-related mortality. Another possible flaw of our study was, as previously discussed, the study patients’ selection. As our cohort was hospital-based, the patients may not be representative of the general type 2 diabetic population of Rio de Janeiro. 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PII: S0168-8227(06)00163-X doi:10.1016/j.diabres.2006.04.008 © 2006 Elsevier Ireland Ltd. All rights reserved. | |
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