Association of Hyperglycemia on Admission and During Hospitalization with Mortality in Diabetic Patients Admitted for Pneumonia

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1 ORIGINAL ARTICLE Association of Hyperglycemia on Admission and During Hospitalization with Mortality in Diabetic Patients Admitted for Pneumonia Yu Hirata 1, Hiromi Tomioka 2, Reina Sekiya 2, Shyuji Yamashita 2, Toshihiko Kaneda 2, Yoko Kida 2, Chihiro Nishio 2, Masahiro Kaneko 2, Hiroshi Fujii 2 and Takehiro Nakamura 1 Abstract Objective Information available on the clinical features and outcomes of pneumonia in diabetic patients is limited. There are no data on the association between glycemic control during hospitalization and mortality in this population. The objective of this study is to examine whether the presence of hyperglycemia on admission and during hospitalization is associated with mortality in diabetic patients admitted to the hospital for pneumonia. Methods This study is a retrospective observational cohort study of diabetic adults hospitalized for the first time for pneumonia between 2005 and 2011 in a 358-bed community hospital. Univariate and multivariate analyses were performed for 30-day all-cause hospital mortality adjusted for sex, age, type of pneumonia (community-acquired pneumonia or nursing and health care-associated pneumonia), severity of pneumonia according to the A-DROP score and various comorbidities in consideration of the serum glucose and hemoglobin A1c levels on admission and the mean plasma glucose level during hospitalization. Results Of the 1,499 pneumonia patients evaluated, 185 (12.3%) (mean age 75 years) had diabetes mellitus. Fourteen (7.6%) of the 185 diabetic patients died within 30 days after admission. According to the univariate analysis, 30-day mortality was significantly associated with the A-DROP score (p<0.0001), the admission glucose level (p=0.01) and the mean plasma glucose level during hospitalization (p<0.0001). Even after adjusting for factors related to the severity of pneumonia, the mean plasma glucose level during hospitalization remained significantly associated with 30-day mortality (p=0.004). Conclusion Hyperglycemia determined according to the mean plasma glucose level during hospitalization is independently associated with 30-day all-cause hospital mortality in diabetic patients admitted for pneumonia. Key words: diabetes mellitus, pneumonia, hyperglycemia, mortality (Intern Med 52: , 2013) () Introduction Pneumonia is one of the most common infectious lung diseases in the more economically developed countries and is associated with considerable morbidity and mortality. Pneumonia ranks among the five major causes of death worldwide, despite the availability of potent antibiotic therapy, and is now the third leading cause of death in Japan. An increasing age is consistently identified as a risk factor for death due to pneumonia, a disease classically called the old man s friend. Diabetes mellitus, a highly prevalent chronic metabolic disorder that is present in approximately 5% to 10% of the elderly population, is thought to be a risk factor for pneumonia (1-4). Diabetic individuals may have increased susceptibility to pneumonia for several reasons. They are at increased risk for aspiration, hyperglycemia, decreased immu- Department of Diabetes and Endocrinology, Kobe City Medical Center West Hospital, Japan and Department of Respiratory Medicine, Kobe City Medical Center West Hospital, Japan Received for publication December 24, 2012; Accepted for publication June 12, 2013 Correspondence to Dr. Hiromi Tomioka, htomy@kobe-nishishimin-hospi.jp 2431

2 nity, an impaired lung function, pulmonary microangiopathy and coexisting morbidities (5). Several aspects of immunity, such as the polymorphonuclear leukocyte function (i.e., leukocyte adherence, chemotaxis and phagocytosis) and bactericidal activity in the serum are depressed in patients with diabetes (6-8). Glycemic control worsens in the presence of infection (9). Diabetes (vs. no diabetes) is also associated with death from pneumonia and other infectious diseases (10-13). In Japan, infectious disease is the third most frequent cause of death, accounting for 14.3% of all-cause deaths in patients with diabetes (14). Respiratory infections account for 41% of all infections in patients with diabetes (15). Unfortunately, the information available on the clinical features and outcomes of pneumonia in diabetic patients is limited. In particular, we are aware of no data regarding the analysis of glycemic control during hospitalization and the outcomes of pneumonia in patients with diabetes. We therefore analyzed the clinical findings and outcomes of pneumonia in patients with diabetes mellitus. The key question addressed in this study is whether hyperglycemia at the time of presentation or during hospitalization is associated with the outcomes in diabetic patients with pneumonia. Materials and Methods Study design and subjects This study was performed according to the Japanese ethical guidelines for epidemiologic research and was approved by the Institutional Review Board of Kobe City Medical Center West Hospital with a waiver for informed consent. We conducted a retrospective observational cohort study of adult diabetic patients admitted to Kobe City Medical Center West Hospital (a 358-bed community hospital in Kobe City, Hyogo, Japan) for the treatment of pneumonia between 2005 and Patients with hospital-acquired pneumonia (HAP) were excluded. The primary outcome of this study was 30-day all-cause hospital mortality after admission. Previous research has shown that 30-day mortality in patients hospitalized with pneumonia is primarily due to the pneumonia rather than coexisting comorbid conditions (16). Definitions We categorized the study patients into Community- Acquired Pneumonia (CAP) or Nursing and Health care- Associated Pneumonia (NHCAP) groups. NHCAP and CAP were defined according to the Japanese Respiratory Society (JRS) guidelines (17, 18). NHCAP was determined based on the presence of any of the following conditions: residence in a long-term nursing home setting or health care home; discharge from the hospital within the preceding 90 days; an elderly or physically disabled status requiring health care; and the need for continuous endovascular therapy in an ambulatory setting (including dialysis, antibiotics, anticancer drugs and immunosuppressants). The patients were classified into the CAP group if they did not meet the criteria for NHCAP. The presence of diabetes mellitus was based on a previous clinical and/or biochemical diagnosis of diabetes mellitus and/or treatment with oral antidiabetic agents or insulin. Alternatively, the diagnosis was established during an episode of pneumonia when the fasting plasma glucose concentration was 126 mg/dl and/or 200 mg/dl after a meal on two or more separate occasions. Diabetes was classified as type 1, type 2 or due to other specific mechanisms or diseases according to the Report of the Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes Mellitus (19). The duration of diabetes was computed as the time elapsed between the first record of treatment of diabetes and the admission date for pneumonia. The hemoglobin A1c (HbA1c) levels (if measured within one month before or one week after admission) are shown according to the National Glycohemoglobin Standardization Program (NGSP) levels (20). The levels of glucose were obtained either during fasting or before meals according to the patient s self monitoring of blood glucose and standard blood tests and evaluations of arterial blood drawn for blood gas analyses. The mean plasma glucose level during hospitalization was determined by averaging the numerical values obtained from these tests. The subjects were defined as having hypoglycemia during hospitalization if their serum glucose level was <70 mg/dl at one or more time points (21). Evaluation of the severity of pneumonia The severity of pneumonia was evaluated using predictive rules according to the 6-point scale (0-5) proposed by the JRS: A-DROP (17). The A-DROP scoring system assesses the following parameters: (i) age (men 70 years, women 75 years); (ii) dehydration (blood urea nitrogen 21 mg/l); (iii) respiratory failure (SaO2 90% or PaO2 60 mmhg); (iv) orientation disturbance (confusion); and (v) low blood pressure (systolic blood pressure 90 mmhg). Clinical evaluation of the patients On admission, a complete clinical history was obtained, and a physical examination, chest radiography and basic chemistry and hematology tests were performed. The presence of comorbid conditions was determined according to patient reports and medical record reviews. Data from medical records were obtained on the need for invasive or noninvasive mechanical ventilation, length of hospital stay and survival outcome (survival or death) 30 days after admission. Microbiological studies The microbiological evaluations included the following tests: blood aerobic and anaerobic conventional cultures of two samples; Gram staining and cultures of sputum when available; and a rapid test (Binax NOW, Binax, Inc., Scar- 2432

3 Table 1. Demographic Characteristics of Diabetic Patients Admitted to Hospital for Pneumonia CAP patients (n=87) NHCAP patients (n=98) Total (n=185) Age*, y 69.4 ± ± ± 12.4 Male sex 62 (71.3) 61 (62.2) 123 (66.5) Smoking* Never 29 (33.3) 71 (72.5) 100 (54.1) Past smoker 30 (34.5) 24 (24.5) 54 (29.2) Current smoker 28 (32.2) 3 (3.1) 31 (16.8) Alcohol consumption* Never 46 (52.9) 85 (86.7) 131 (70.8) Regular 26 (29.9) 3 (3.1) 29 (15.7) Occasional 15 (17.2) 10 (10.2) 25 (13.5) Comorbidities Congestive heart failure 7 (8.1) 19 (19.4) 26 (14.1) Chronic pulmonary disease 28 (32.2) 20 (20.4) 48 (25.9) Cerebrovascular disease 24 (27.6) 47 (48.0) 71 (38.4) Dementia* 2 (2.3) 35 (35.7) 37 (20.0) Chronic liver disease 9 (10.3) 8 (8.2) 17 (9.2) Chronic renal disease 12 (13.8) 16 (16.3) 28 (15.1) Malignant tumor 19 (21.8) 25 (25.5) 44 (23.8) A-DROP score* 1.8 ± ± ± (10.3) 3 (3.1) 12 (6.5) 1 31 (35.6) 11 (11.2) 42 (22.7) 2 25 (28.7) 35 (35.7) 60 (32.4) 3 17 (19.5) 30 (30.6) 47 (25.4) 4 2 (2.3) 16 (16.3) 18 (9.7) 5 3 (3.5) 3 (3.1) 6 (3.2) Admission glucose, mg/dl ± ± ± Hemoglobin A1c, % 8.2 ± ± ± 2.0 Mean glucose, mg/dl ± ± ± 56.8 Hypoglycemia 11 (12.6) 11 (11.3) 22 (12.0) Data are presented as number (%) or mean ± SD. CAP: community-acquired pneumonia, NHCAP: nursing and healthcare-associated pneumonia *p<0.0001, p<0.05, p<0.005 between CAP and NHCAP Hemoglobin A1c was evaluated in 151 of the 185 study patients (77 CAP patients and 74 NHCAP patients). borough, ME, USA) for urinary antigens of Streptococcus pneumoniae or Legionella pneumophila serogroup 1. Statistical analysis All analyses were performed using the JMP statistical software program (SAS Institute Inc., Cary, NC, USA). Categorical variables were analyzed using the χ2-test or Fisher s exact test. Continuous variables were compared using Student s t-test when the variables were normally distributed and the Mann-Whitney U test when the variables were non-normally distributed. A univariate logistic regression analysis was applied to determine which factors were associated with 30-day mortality. The contribution of each potential risk factor was denoted by an odds ratio (OR) and associated 95% confidence interval (CI). A multivariate logistic regression analysis was performed for variables associated with 30-day mortality according to the univariate analysis (p<0.1). A value of p<0.05 was considered to be statistically significant. Patient characteristics Results During the study period, 1,499 patients were evaluated (CAP group: 610, NHCAP group: 889). A total of 87 (14.3%) of the 610 CAP patients and 98 (11.0%) of the 889 NHCAP patients had diabetes mellitus, with no significant differences between the groups. Table 1 shows the demographic characteristics of the patients. The study population was 66.5% male and 33.5% female, with a mean age of 75 years. The median duration of diabetes was seven years in 97 patients, with such information unavailable for the remaining 88 patients. An initial diagnosis of diabetes mellitus was established in 14 patients during the episode of pneumonia described in this report. According to the classification proposed by the Japan Diabetes Society (19), 183 patients had type 2 diabetes, and the remain- 2433

4 Table 2. First-line Antimicrobials and Clinical Outcomes CAP patients (n=87) NHCAP patients (n=98) Total (n=185) Initial antimicrobials Penicillins 75 (86.2) 83 (84.7) 158 (85.4) Cephalosporins 4 (4.6) 6 (6.1) 10 (5.4) Tetracycline 1 (1.1) 1 (1.0) 2 (1.1) Macrolides 8 (9.2) 2 (2.0) 10 (5.4) Carbapenems 8 (9.2) 10 (10.2) 18 (9.7) Fluoroquinolone 11 (12.6) 4 (4.1) 15 (8.1) Others 9 (10.3) 9 (9.2) 18 (9.7) Need for mechanical ventilation 9 (10.3) 6 (6.1) 15 (8.1) Length of hospital stay*, median, days Mortality within 30 days 6 (6.9) 8 (8.2) 14 (7.6) Data are presented as number (percentage) unless otherwise specified. CAP: community-acquired pneumonia, NHCAP: nursing and healthcare-associated pneumonia * p<0.0005, between CAP and NHCAP ing two patients had glucocorticoid-induced diabetes mellitus. The patients with NHCAP were significantly older than those with CAP (p<0.0001); however, the male/female ratio did not differ between the two groups. Among the comorbid conditions, congestive heart failure, cerebrovascular disease and dementia were significantly more frequent in the patients with NHCAP than in those with CAP (p<0.05, p< and p<0.0001, respectively). Severity of pneumonia The severity of pneumonia was assessed according to the A-DROP scoring system (17) (Table 1). The average A- DROP score in the NHCAP group was significantly higher than that in the CAP group (CAP 1.8±1.2 vs. NHCAP 2.6± 1.1, p<0.0001). Data for diabetes The mean plasma glucose level on admission and the average mean plasma glucose level during hospitalization were 230.5±112.1 mg/dl (range: mg/dl) and 176.8±56.8 mg/dl (range: mg/dl), respectively. In 151 of the 185 patients, the HbA1c level was evaluated, which ranged from 5.3% to 18.6% (mean: 8.0±2.0%). Hypoglycemic episodes during hospitalization were noted in 12.0% of the patients. No significant differences in these data were observed between the two patient groups. Distribution of microorganisms Laboratory sputum cultures were obtained in 132 patients (59/87 CAP patients and 73/98 NHCAP patients). The most common microorganisms in the sputum cultures were Staphylococcus aureus (n=16) followed by Pseudomonas aeruginosa (n=14), Streptococcus pneumoniae (n=7) and Klebsiella pneumoniae (n=7). Streptococcus pneumoniae was, however, the leading pathogen (n=22) identified according to urinary antigen testing. Only one patient with CAP was diagnosed with Legionella pneumonia based on positive urinary antigen testing. Clinical outcomes Table 2 shows the initial antibiotic treatments and clinical outcomes of the study patients. The initial antibiotics were prescribed according to the JRS CAP guidelines (17). Most commonly, CAP and NHCAP patients received penicillins. The frequency of the type of antibiotics used did not differ between the CAP and NHCAP groups. The median length of hospital stay was longer in the NHCAP patients than in the CAP patients (CAP 12 days vs. NHCAP 22.5 days, p< 0.005). Fourteen (7.6%) of the 185 patients died within 30 days after admission. The 30-day mortality was not significantly different between the CAP and NHCAP groups (CAP 6.9% vs. NHCAP 8.2%). Risk factors for mortality Risk factors for 30-day mortality were investigated utilizing the demographic characteristics of the patients. In the univariate analysis, 30-day mortality was significantly associated with the A-DROP score (p<0.0001), the admission glucose level (p=0.01) and the mean plasma glucose level during hospitalization (p<0.0001) (Table 3). According to the multivariate analysis, 30-day mortality was significantly associated with the A-DROP score (OR 3.99; 95% CI: , p=0.0001) and the mean plasma glucose level during hospitalization (per 1 mg/dl) (OR 1.02; 95% CI: , p=0.004) (Table 4). Discussion The results showed that 185 (12.3%) of the 1,499 pneumonia patients in our cohort had diabetes mellitus, and the multivariate analysis revealed that the 30-day mortality after admission for pneumonia was not related to hyperglycemia at presentation but was related to hyperglycemia determined according to the mean plasma glucose level during hospitalization. No prior published studies have examined the association between hyperglycemia during hospitalization and 2434

5 Table 3. Univariate Analysis of Factors Associated with 30-Day Mortality Survival (n=171) Death (n=14) n (%) n (%) p OR (95% CI) NHCAP 90 (52.6) 8 (57.1) ( ) Age, y 75.0 ± ± ( ) Male sex 112 (65.5) 11 (78.6) ( ) Congestive heart failure 24 (14.0) 2 (14.3) ( ) Chronic pulmonary disease 46 (26.9) 2 (14.3) ( ) Cerebrovascular disease 66 (38.6) 5 (35.7) ( ) Dementia 33 (19.3) 4 (28.6) ( ) Chronic liver disease 15 (8.8) 2 (14.3) ( ) Chronic renal disease 26 (15.2) 2 (14.3) ( ) Malignant tumor 42 (24.6) 2 (14.3) ( ) A-DROP score 2.1 ± ± 0.9 < ( ) Admission glucose, mg/dl ± ± ( ) Hemoglobin A1c*, % 7.9 ± ± ( ) Mean glucose, mg/dl ± ± 65.5 < ( ) Hypoglycemia 18 (10.6) 4 (28.6) ( ) Data are presented as number (percentage) or mean ± SD. Statistical analyses were performed using the survival group as a comparison. NHCAP: nursing and healthcare-associated pneumonia, CI: confidence interval, OR: odds ratio. Hemoglobin A1c was evaluated in 151 of the 185 study patients (140 survivors and 11 deaths). Table 4. Results of the Multivariable Logistic Regression Analysis for 30-Day Mortality OR (95% CI) p A-DROP score (per score) 3.99 ( ) Admission glucose (per 1mg/dL) 1.00 ( ) 0.35 Hemoglobin A1c (per 1%) 1.05 ( ) 0.75 Mean glucose (per 1mg/dL) 1.02 ( ) Hypoglycemia (yes/no) 1.01 ( ) day mortality in diabetic patients with pneumonia. Our study is the first to show an association between glycemic control during hospitalization and mortality in this population. In patients with CAP, diabetes mellitus is one of the most common underlying diseases (10, 13, 22-25), with a reported prevalence of 6-25% among those with CAP. In our study population, 87 of the 610 CAP patients had diabetes mellitus (14.3%), a proportion that is in accordance with the findings of previous reports on comorbid conditions in CAP patients. We also analyzed another population with pneumonia, patients with NHCAP. This is a new category documented in the 2011 JRS Guidelines (18). NHCAP is distinct from CAP and is a Japanese variant of health careassociated pneumonia (26) in terms of the Japanese population, taking into consideration the health care insurance system, including the nursing care insurance system and the pattern of drug-resistant pathogens (18). Although the frequency of diabetes mellitus as an underlying disease has not been sufficiently evaluated among patients with NHCAP, diabetes mellitus is speculated to be a common underlying disease in patients with NHCAP, as in the case of CAP (10, 13, 22-25). Recent studies in Japan have reported a prevalence of diabetes in patients with NHCAP of 13% (27) in a university hospital and 11% (27) and 20.6% (28) in community hospitals. In our population, 98 of the 889 NHCAP patients (11.0%) had diabetes mellitus, a proportion in accordance with the findings of these reports. The prevalence of diabetes did not differ between the CAP and NHCAP groups in our population, in accordance with previous results (27, 28). A population-based cohort study indicated that poor longterm glycemic control in patients with diabetes clearly increases the risk of hospitalization for pneumonia (4, 29). Kornum et al. (29) found that, compared with not having diabetes, having diabetes in combination with an HbA1c level of 9% is associated with a 60% increased risk of pneumonia-related hospitalization and having diabetes in combination with an HbA1c level of 7% is associated with a 22% increased risk. Ehrlich et al. (4) also reported that the risk of pneumonia increases significantly with increasing HbA1c values. These results confirm observations from in vitro studies in which hyperglycemia has been found to be associated with abnormalities in the neutrophil function, such as impaired chemotaxis, phagocytosis and bacterial killing (30). Hyperglycemia may also occur in nondiabetic patients with acute infections. Cytokines, including IL-1, IL-6, IL-10 and TNF-α, can contribute to elevated glucose levels by stimulating gluconeogenesis and increasing insulin resistance in the liver and peripheral tissue (31-33). As part of the stress response, the release of cortisol and endogenous substances is likely to contribute to hyperglycemia as well. Therefore, in any individual patient, a high plasma glucose level at the time of admission for pneumonia may reflect either a diabetic condition that has predisposed the patient to 2435

6 the infection or may have resulted from cytokine release, which reflects the severity of the infection. Individual risk factors for pneumonia and risk scoring systems for assessing mortality from pneumonia have attracted considerable interest. The most extensive study (34) on the prognosis of CAP found the plasma glucose level in the blood to be an independent risk factor for mortality. McAlister et al. (35) reported that hyperglycemic patients (admission blood glucose 200 mg/dl) with CAP exhibit increased mortality in comparison with normoglycemic individuals. There is, however, little evidence to suggest that the serum glucose level on admission is associated with mortality in patients with preexisting diabetes. In our multivariate analysis, among the diabetic patients admitted with pneumonia, including CAP, the serum glucose level on admission was not associated with mortality. Kornum et al. (11) reported that, in their study, a high serum glucose level on admission was a predictor of death among patients with diabetes and that the impact of hyperglycemia on mortality was lower in patients with type 2 diabetes than in nondiabetic individuals. Their study differed from ours in that their cohort included both CAP and HAP patients and the glucose levels on admission or the following day were available. Therefore, the results of Kornum et al. (11) are difficult to interpret. Rueda et al. (36) reported that, in their study of nondiabetic patients admitted with pneumococcal pneumonia, there was a strong association of the severity of pneumonia and mortality with the admission serum glucose level, whereas, in diabetic patients, the severity of pneumonia and mortality was not related to the degree of hyperglycemia on admission. Falguera et al. (12) prospectively studied the outcomes of 106 diabetic patients from among 660 consecutive cases of CAP and showed that the presence of multilobar infiltrates and the simultaneous occurence of comorbidities were independently associated with mortality among the 106 diabetic patients. No relationships were found with age, sex, duration of diabetes, period from diagnosis of diabetes, the glucose level, the HbA1c level, insulin therapy during pneumonia, bacteremia, pleural effusion or empyema and/or complicated effusion. Although Lepper et al. (13) reported that patients with pneumonia and preexisting diabetes exhibit significantly increased overall mortality compared to those without diabetes, the outcomes were not significantly affected by the serum glucose levels on admission. Our results are consistent with the findings of these studies in that the plasma glucose level on admission was not found to be associated with pneumonia-related mortality among the diabetic patients admitted with pneumonia. In diabetic patients, the height of the plasma glucose level on admission may be more closely related to the underlying state of diabetic control and cannot be specifically linked to extreme cytokine release (36). Patients with diabetes may in part be protected from acute glucose toxicity (37, 38). Based on these studies, hyperglycemia is associated with a greater disease severity and worse outcomes in patients without diabetes; however, this finding cannot be extended to individuals with diabetes. No policy for diabetes treatment in patients with pneumonia is universally available. Due to the evidence showing that better glycemic control improves immune mechanisms and reduces the predisposition to and severity of infection (39, 40), clinicians should pay attention to the glucose level during hospitalization. In previous studies, changes in the serum glucose levels during hospitalization were not examined; therefore, the results were based only on admission serum glucose values, and it is likely that the risks associated with hyperglycemia among diabetic patients during admission for pneumonia were underestimated. The present results showed that, even after adjusting for factors related to the severity of pneumonia, the mean plasma glucose level during hospitalization remained significantly associated with 30-day mortality. These findings provide direction for future studies to aid in the management of diabetic patients admitted to the hospital with pneumonia. It is not known whether stricter control of plasma glucose during hospitalization would improve the outcomes of pneumonia in diabetic patients. However, it is worth noting that, in a recent study of intensive glucose control with a target blood glucose range of 81 to 108 mg/dl in critically ill patients, intensive control of the blood glucose level was found to be associated with a higher incidence of significant hypoglycemia as well as increased mortality (41). Determining the target for glycemic control in the elderly, especially in patients with NHCAP, is a complex care issue. Patients with NHCAP are usually elderly, frail, disabled, cognitively impaired or have a limited ability to communicate and are at a particularly high risk for hypoglycemia. Close attention should be paid to glycemic control, especially in hospitalized NHCAP patients with diabetes. Our study has several potential shortcomings. First, the study was limited to one medical center; therefore, the small sample size weakens the power of the study. Second, our study was retrospective and therefore subject to the recognized limitations of this study design, including bias and incomplete data. In addition, we were unable to control for the timing of the HbA1c examination and the antidiabetes medications received during admission. Third, we cannot exclude the posibility that our population may have included patients with temporal hyperglycemia as part of the stress response that can occur in nondiabetic patients. Finally, although we relied on the mean plasma glucose level during hospitalization as our measure of glucose control, it may have been more beneficial to measure glucose control using a broader based measure, such as the time-weighted blood glucose level (41) or the hyperglycemic index (42). Conclusion The present study showed that hyperglycemia determined according to the mean plasma glucose level during hospitalization is independently associated with mortality in diabetic patients admitted to the hospital for pneumonia. It is not known whether stricter control of plasma glucose during 2436

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