The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies

Abstract

Background: Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear.

Methods: A retrospective analysis of two multicentre cohorts was carried out. The effect of pre-existing diabetes on the host immune response, acute organ function and mortality in patients hospitalised with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalisations in the population-based cohort study, Health ABC (n=1639) was determined. Measurements included the mortality rate within the first year, risk of organ dysfunction, and immune responses, including circulating inflammatory (tumour necrosis factor, interleukin 6, interleukin 10), coagulation (Factor IX, thrombin-antithrombin complexes, antithrombin), fibrinolysis (plasminogen-activator inhibitor-1 and D-dimer) and cell surface markers (CD120a, CD120b, human leucocyte antigen (HLA)-DR, Toll-like receptor-2 and Toll-like receptor-4).

Results: In GenIMS, diabetes increased the mortality rate within the first year after CAP (unadjusted HR 1.41, 95% CI 1.12 to 1.76, p=0.002), even after adjusting for pre-existing cardiovascular and renal disease (adjusted HR 1.3, 95% CI 1.03 to 1.65, p=0.02). In Health ABC, diabetes increased the mortality rate within the first year following CAP hospitalisation, but not after hospitalisation for non-infectious illnesses (significant interaction for diabetes and reason for hospitalisation (p=0.04); HR for diabetes on mortality over the first year after CAP 1.87, 95% CI 0.76 to 4.6, p=0.16, and after non-infectious hospitalisation 1.16, 95% CI 0.8 to 1.6, p=0.37). In GenIMS, immediate immune response was similar, as evidenced by similar circulating immune marker levels, in the emergency department and during the first week. Those with diabetes had a higher risk of acute kidney injury during hospitalisation (39.3% vs 31.7%, p=0.005) and they were more likely to die due to cardiovascular and kidney disease (34.4% vs 26.8% and 10.4% vs 4.5%, p=0.03).

Conclusions: Pre-existing diabetes was associated with a higher risk of death following CAP. The mechanism is not due to an altered immune response, at least as measured by a broad panel of circulating and cell surface markers, but may be due to worsening of pre-existing cardiovascular and kidney disease.

Figure 1

Failure plots over 1 year showing higher risk of death for subjects with diabetes compared to those without diabetes following hospitalization for community acquired pneumonia in GenIMS.

Figure 2

No differences were observed in geometric means of inflammatory (tumor necrosis factor [TNF], interleukin (IL)-6, and IL-10 shown in Panel A), coagulation (Factor IX, antithrombin, and thrombin-antithrombin [TAT) complexes shown in Panel B), and fibrinolysis (plasminogen activator [PAI]-1 and D-dimer shown in Panel C) biomarkers in 1427, 734, and 734 subjects with and without diabetes, respectively. Biomarkers were measured on presentation to the emergency department and over the first week of hospitalization and p values are shown for these comparisons.

Figure 2

No differences were observed in geometric means of inflammatory (tumor necrosis factor [TNF], interleukin (IL)-6, and IL-10 shown in Panel A), coagulation (Factor IX, antithrombin, and thrombin-antithrombin [TAT) complexes shown in Panel B), and fibrinolysis (plasminogen activator [PAI]-1 and D-dimer shown in Panel C) biomarkers in 1427, 734, and 734 subjects with and without diabetes, respectively. Biomarkers were measured on presentation to the emergency department and over the first week of hospitalization and p values are shown for these comparisons.

Figure 2

No differences were observed in geometric means of inflammatory (tumor necrosis factor [TNF], interleukin (IL)-6, and IL-10 shown in Panel A), coagulation (Factor IX, antithrombin, and thrombin-antithrombin [TAT) complexes shown in Panel B), and fibrinolysis (plasminogen activator [PAI]-1 and D-dimer shown in Panel C) biomarkers in 1427, 734, and 734 subjects with and without diabetes, respectively. Biomarkers were measured on presentation to the emergency department and over the first week of hospitalization and p values are shown for these comparisons.

Figure 3

No differences were observed in cell surface markers on presentation to the emergency department and on third and seventh day in subjects with and without diabetes in 624 subjects. Values for cell surface markers were reported as the mean channel fluorescence (MCF) of cells positive for a given cell surface marker. P values are shown for comparisons over time. Only expression of TLR2 on granulocytes appeared to be higher among subjects with diabetes on day 1 and 3 and were higher in those without diabetes on day 7 (p=0.04).