Blood glucose, diabetes and metabolic control in patients with community-acquired pneumonia

To the Editor:We read with interest the studies by Cariou et al [1] andWang et al [2] published in the journal. Evidence so far suggests that type 2 diabetes mellitus may not increase the overall risk of an infection with the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) [3], the causal agent of a syndrome called coronavirus disease2019 (COVID-19); however, pre-existing type 2 diabetes appears to be associated with more severe infection [4]. Moreover, recent evidence by Zhu et al [5] and data from an observational NHS England cohort [6, 7], consistently showed an increased risk for COVID-19-related death in patients with type 2 diabetes. The study by Cariou et al [1] adds to current knowledge by reporting that higher BMI (but not long-term glycaemic control or type of glucose-lowering therapy used) was significantly associated with the severity of COVID-19 infection as studied in their cohort of 1317 patients with pre-existing diabetes (89% with type 2 diabetes). Wang and colleagues analysed whether blood glucose taken within 24 h of admission after a fasting period was a predictive marker for 28-day mortality in 605 COVID-19 patients without diabetes [2]. They found that patients with fasting serum glucose concentrations ≥7.0 mmol/l had a significantly higher risk of death (HR 2.30; 95% CI 1.49, 3.55; p = 0.0002). Hence, currently available evidence on clinical risk management in patients with COVID-19 strongly supports the inclusion of assessment of diabetes status as well as careful consideration of additional clinical attributes, such as BMI and blood glucose levels. These important insights may have just recently emerged for COVID-19; however, previous evidence in clinical community-acquired pneumonia (CAP) research has already identified the importance of pre-existing diabetes for outcome risk assessment. We conducted a large prospective study in 6891 Caucasian patients admitted for CAP due to causes other than SARS-CoV2 to 12 German centres [8]. We explored whether pre-existing diabetes would be associated with an increased mortality risk from CAP caused by any infectious agent [8]. The 28-day mortality risk was significantly increased in the 1114 participants with diabetes compared with that in individuals without diabetes with normal serum glucose levels (adjusted HR 1.92; 95% CI 1.34, 2.75; p < 0.001). Notably, evidence for assessing COVID-19 mortality risk has recently expanded beyond exploring diabetes status and indicated that assessing blood glucose levels could further identify at-risk individuals for adverse outcomes. Cariou and colleagues report an ageand sex-independent association between increased admission plasma glucose levels and the severity of COVID-19, as well as early mortality at day 7, among individuals with diabetes [1]. In our previous study we also utilised admission glucose values to further categorise patients into normoand hyperglycaemic subgroups [8]. This * Philipp M. Lepper philipp.lepper@uks.eu

with pre-existing diabetes (89% with type 2 diabetes). Wang and colleagues analysed whether blood glucose taken within 24 h of admission after a fasting period was a predictive marker for 28-day mortality in 605 COVID-19 patients without diabetes [2]. They found that patients with fasting serum glucose concentrations ≥7.0 mmol/l had a significantly higher risk of death (HR 2.30; 95% CI 1.49, 3.55; p = 0.0002). Hence, currently available evidence on clinical risk management in patients with COVID-19 strongly supports the inclusion of assessment of diabetes status as well as careful consideration of additional clinical attributes, such as BMI and blood glucose levels.
These important insights may have just recently emerged for COVID-19; however, previous evidence in clinical community-acquired pneumonia (CAP) research has already identified the importance of pre-existing diabetes for outcome risk assessment. We conducted a large prospective study in 6891 Caucasian patients admitted for CAP due to causes other than SARS-CoV2 to 12 German centres [8]. We explored whether pre-existing diabetes would be associated with an increased mortality risk from CAP caused by any infectious agent [8]. The 28-day mortality risk was significantly increased in the 1114 participants with diabetes compared with that in individuals without diabetes with normal serum glucose levels (adjusted HR 1.92; 95% CI 1.34, 2.75; p < 0.001).
Notably, evidence for assessing COVID-19 mortality risk has recently expanded beyond exploring diabetes status and indicated that assessing blood glucose levels could further identify at-risk individuals for adverse outcomes. Cariou and colleagues report an age-and sex-independent association between increased admission plasma glucose levels and the severity of COVID-19, as well as early mortality at day 7, among individuals with diabetes [1]. In our previous study we also utilised admission glucose values to further categorise patients into normo-and hyperglycaemic subgroups [8]. This glucose-based stratification allowed us to identify individuals at further increased risk for CAP mortality. Compared with participants with normal plasma glucose levels and without diabetes at admission, the adjusted HR for death within 28 days after admission in those with diabetes was 1.92 (95% CI 1.34, 2.75; p < 0.001) and the observed mortality risk remained largely unchanged for up to 180 days of follow-up [8].
Importantly, the clinical utility of glucose levels on admission appears to extend to CAP patients without pre-existing diabetes. The study by Wang et al [2], as well as our previous study [8], found a significant association between admission glucose and CAP mortality outcome in individuals without known diabetes. We reported that glucose levels on admission in patients admitted for CAP but without pre-existing diabetes (n = 5141) were significantly associated with all-cause mortality. In non-diabetic individuals 28-and 90-day mortality was increased whether glucose concentrations were assessed by a specific glucose threshold level (i.e. ≥6.0 mmol/l on admis-  [2]. Thus, the available evidence shows that mortality risk from CAP (including COVID-19) is considerably increased in individuals with pre-existing diabetes, but also under conditions of acutely elevated blood glucose levels, even in patients without previously diagnosed diabetes. Based on these results, clinical risk assessment based on pre-existing diabetes status in individuals with COVID-19 is essential. If diabetes is present, BMI, as well as rigorous and serial assessments of inhospital glucose levels (defined as at least one documented 2 h post-prandial glucose value exceeding 10 mmol/l) could add further value for risk stratification [5]. However, it may be difficult to obtain this information within a useful timeframe for the latter, and we suggest that a single point-of-care measurement of glucose, especially at standardised timepoints (i.e. at hospital admission without a fasting period) could be an attractive alternative. Notably, hospital admission glucose may be of particular importance for people presenting with COVID-19 without pre-existing diabetes, as this clinical marker could identify at-risk individuals that may easily be missed by solely assessing diabetes status.
In summary, evidence from large CAP cohorts (including patients with and without COVID-19) from different geographical regions and ethnic groups, strongly suggests that individuals with pre-existing diabetes and/or elevated blood glucose levels need special attention when presenting to a hospital, as they represent a group at high risk for increased mortality (Table 1). We believe admission glucose could represent an attractive clinical tool for early and effective CAP risk assessment as it is readily available in daily practice. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.