Participants
Between August 1st, 2021 and April 10th, 2022 a total of 1254 hospitalized patients were assessed for eligibility at five hospitals. Of these, 1152 patients were enrolled in the study and subsequently analysed. Anti-SARS-CoV2-spike antibody levels were measured in all 1152 patients. Additional parameters such as creatinine and NT-proBNP could only be measured in 1046 patients due to insufficient residual sample material. Patient flow is outlined in Fig. 1.
Of the study population, 118 patients did not survive, 165 patients were admitted to an intensive care unit, 47 patients required endotracheal intubation and 587 patients required oxygen administration. 275 patients either had a history of diabetes or were diagnosed during their hospital stay. Table 1 shows patient characteristics by diabetes status for diabetic, non-diabetic and matched, non-diabetic patients. Table 2 outlines patient characteristics and outcomes by vaccination status.
In comparison to non-diabetic patients, diabetic patients were on average 11 years older and had significantly higher BMIs. Diabetic patients also had significantly higher rates of hypertension, coronary artery disease, heart failure, chronic obstructive pulmonary disease, renal diseases and cerebrovascular disease. Mortality rates, ICU admission and oxygen adminsitration were significantly higher in diabetic patients than in non-diabetic patients.
In order to increase comparability between diabetic and non-diabetic patients, we conducted propensity score matching. Compared to matched, non-diabetic patients, diabetic patients still registered higher rates of mortality, ICU admission and oxygen administration, albeit the differences were no longer statistically significant.
Anti-SARS-CoV2 antibody levels by outcome
Anti-SARS-Cov2 spike antibody levels were significantly lower in non-survivors than in survivors across all investigated patient subgroups – including diabetic patients, non-diabetic patients and matched, non-diabetic patients (U/ml; diabetic mean 351, 95%CI 106–595 vs. 1123, 968–1279, p < 0.001; non-diabetic 511, 281–742 vs. 968, 888–1048, p < 0.001; matched, non-diabetic 246, 0-507 vs. 920, 761–1079, p < 0.001). This association continued to be statistically significant after stratification of diabetic patients by vaccination status (diabetic vaccinated 846, 302–1390 vs. 1618, 1438–1799, p = 0.006 and diabetic non-vaccinated 8, 0–21 vs. 146, 20–273, p = 0.014).
Similarly, diabetic, non-diabetic and matched, non-diabetic patients with lower anti-SARS-CoV2 spike antibodies were more likely to be admitted to an intensive care unit than patients with higher levels (U/ml; diabetic mean 659, 363–955 vs. 1081, 923–1238, p = 0.011; non-diabetic 458, 283–632 vs. 998, 916–1080, p < 0.001; non-diabetic, matched 195, 0-397 vs. 974, 807–1139, p < 0.001). However, antibody levels did not differ significantly in vaccinated and non-vaccinated diabetic patients with regard to ICU admission.
Similar to in-hospital mortality and intensive care admission, patients who required endotracheal intubation had significantly lower levels of anti-SARS-CoV2 spike antibodies than those who did not (U/ml; diabetic mean 210, 0-592 vs. 1042, 897–1186, p = 0.046; non-diabetic 270, 1-539 vs. 957, 879–1035, p < 0.001; non-diabetic, matched 148, 0-460 vs. 887, 734–1039, p < 0.001).
Finally, lower anti-SARS-CoV2-spike antibody levels were indicative of oxygen administration across all subgroups except non-vaccinated diabetic patients (U/ml; diabetic mean 735, 574–897 vs. 1474, 1234–1715, p < 0.001; non-diabetic 638, 538–737 vs. 1186, 1078–1294, p < 0.001; non-diabetic, matched 608, 440–776 vs. 1166, 918–1414, p < 0.001).
Figure 2 shows antibody levels by outcome, stratified by patient group and vaccination status.
Table 1
Patient characteristics and outcomes for diabetic, non-diabetic and matched, non-diabetic patients. Quantitative results are given as means ± standard deviation. BMI body mass index, DM diabetes mellitus, CAD coronary artery disease, COPD chronic obstructive pulmonary disease, TIA transient ischemic attack, CVD cerebrovascular disease, ICU intensive care unit, intubation- endotracheal intubation, oxygen req - oxygen requirement, CT cycle threshold, spike ab - anti-SARS-CoV2 spike antibodies, bold print- statistically significant.
| whole cohort n = 1152 | DM n = 275 | no DM n = 877 | p-Value | no DM, matched n = 232 | p-Value (DM vs. no DM, matched) |
age (years) | 66.8 ± 20.3 | 75.1 ± 12.2 | 64.2 ± 21.6 | < 0.001 | 71.8 ± 16.3 | 0.101 |
male gender (%) | 53.2 | 53.5 | 53.1 | 0.926 | 50.0 | 0.438 |
BMI (kg/m2) | 27.1 ± 6.5 | 29.1 ± 6.2 | 26.4 ± 6.4 | < 0.001 | 28.0 ± 6.3 | 0.020 |
DM (%) | 23.9 | / | / | / | / | / |
hypertension (%) | 50.5 | 77.5 | 42.1 | < 0.001 | 64.7 | 0.001 |
CAD (%) | 21.6 | 36.4 | 17.0 | < 0.001 | 29.3 | 0.093 |
heart failure (%) | 7.2 | 13.1 | 5.4 | < 0.001 | 8.6 | 0.110 |
COPD (%) | 9.6 | 14.9 | 8.0 | < 0.001 | 13.4 | 0.619 |
asthma (%) | 2.4 | 1.5 | 2.7 | 0.228 | 2.2 | 0.552 |
renal disease (%) | 22.9 | 39.3 | 18.0 | < 0.001 | 29.3 | 0.018 |
stroke/TIA/CVD (%) | 11.7 | 18.9 | 9.5 | < 0.001 | 16.4 | 0.458 |
mortality (%) | 10.2 | 16.0 | 8.4 | < 0.001 | 13.4 | 0.405 |
ICU (%) | 14.3 | 19.6 | 12.7 | 0.004 | 18.5 | 0.753 |
intubation (%) | 4.1 | 5.1 | 3.8 | 0.337 | 7.8 | 0.218 |
oxygen req. (%) | 51.0 | 65.0 | 46.6 | < 0.001 | 59.9 | 0.242 |
CT value | 21.3 ± 6.6 | 20.8 ± 6.6 | 21.4 ± 6.5 | 0.085 | 20.6 ± 6.3 | 0.908 |
creatinine (mg/dl) | 1.25 ± 1.07 | 1.55 ± 1.25 | 1.15 ± 0.99 | < 0.001 | 1.16 ± 0.59 | < 0.001 |
NT-proBNP (pg/ml) | 1971 ± 5297 | 2876 ± 6202 | 1689 ± 4953 | < 0.001 | 1973 ± 5315 | 0.033 |
spike ab (U/ml) | 946 ± 1151 | 999 ± 1175 | 930 ± 1144 | 0.263 | 828 ± 1118 | 0.098 |
Table 2
Patient characteristics and outcomes for vaccinated and non-vaccinated, diabetic patients. Quantitative results are given as means ± standard deviation. BMI body mass index, DM diabetes mellitus, CAD coronary artery disease, COPD chronic obstructive pulmonary disease, TIA transient ischemic attack, CVD cerebrovascular disease, ICU intensive care unit, CT cycle threshold, bold print- statistically significant.
| diabetic, vaccinated n = 172 | diabetic, non- vaccinated n = 103 | p-value |
age (years) | 76.6 ± 10.1 | 72.7 ± 14.9 | 0.068 |
male gender (%) | 56.4 | 48.5 | 0.206 |
BMI (kg/m2) | 28.6 ± 5.9 | 29.9 ± 6.6 | 0.123 |
DM (%) | / | / | / |
hypertension (%) | 80.8 | 71.8 | 0.085 |
CAD (%) | 40.1 | 30.1 | 0.095 |
heart failure (%) | 14.5 | 10.7 | 0.359 |
COPD (%) | 18.6 | 8.7 | 0.026 |
asthma (%) | 1.7 | 1.0 | 0.604 |
renal disease (%) | 47.3 | 26.2 | < 0.001 |
stroke/TIA/CVD (%) | 18.6 | 19.4 | 0.868 |
mortality (%) | 10.5 | 25.2 | 0.001 |
ICU (%) | 14.0 | 29.1 | 0.002 |
endotracheal intubation (%) | 2.3 | 9.7 | 0.007 |
oxygen administration (%) | 57.3 | 77.7 | < 0.001 |
CT value | 20.8 ± 7.1 | 20.8 ± 5.8 | 0.710 |
creatinine (mg/dl) | 1.7 ± 1.5 | 1.3 ± 0.7 | 0.027 |
NT-proBNP (pg/ml) | 3179 ± 6331 | 2357 ± 5979 | 0.010 |
spike antibodies (U/ml) | 1537 ± 1144 | 111 ± 485 | < 0.001 |
Anti-SARS-CoV2-spike antibodies and risk
Next, we aimed to quantify the risk associated with lower anti-SARS-CoV2 antibodies in diabetic, non-diabetic and matched, non-diabetic patients. To that end, we built multiple logistic regression models for our endpoints in-hospital mortality, intensive care, endotracheal intubation and oxygen administration. We further included Cox proportional hazard models for in-hospital mortality in order to provide a second measure of risk. To facilitate interpretation of the results and improve comparability we provide risk measures for both the continuous variable in steps of 100U/ml and after z-score normalization. All models were then adjusted for potential confounders, including age, obesity and SARS-CoV2 variant. Both unadjusted and adjusted odds ratios and hazard ratios are reported to show in how far these covariates affect risk of outcome.
Estimated risks for each outcome and patient group are outlined in supplemental table S1. A graphic representation of the results is provided in Fig. 3.
In-hospital mortality
With regard to the whole study population, risk of in-hospital mortality was 1.7 times higher for each decrement by standard deviation of anti-SARS-CoV2 antibody levels (HR 1.721, 95%CI 1.355–2.188, p < 0.001; aHR 1.695, 95%CI 1.280–2.242, p < 0.001).
In diabetic patients, risk of death was 2.1 times higher with each decrease by standard deviation of anti-SARS-CoV2 antibody levels (HR 2.105, 95%CI 1.366–3.247, p < 0.001). This result remained stable after adjusting for age, obesity and SARS-CoV2 variant (aHR 1.988, 95%CI 1.229–3.215, p = 0.005).
Non-diabetic patients had approximately 1.5 times higher risk of in-hospital mortality with decreasing anti-SARS-CoV2 antibody levels (HR 1.563, 95%CI 1.170–2.088, p = 0.002, aHR 1.533, 1.080–2.179, p = 0.017). After propensity score matching, the risk of in-hospital mortality dropped slightly (HR 1.229, 95%CI 1.068–1.413, p = 0.004, aHR 1.329, 1.138–1.552, p < 0.001).
Secondary endpoints
Next, we investigated the risk of intensive care admission depending on SARS-CoV2 antibody levels. For the whole study population, risk of intensive care admission was 1.4 times higher by each decrease in standard deviation of anti-SARS-CoV2 antibody levels (aOR 1.405, 1.128–1.750). Diabetic patients also had significantly higher risks of requiring intensive care with lower antibody levels (OR 1.466, 95%CI 1.060–2.028), albeit these differences were not robust after adjusting for age, obesity and SARS-CoV2 variant. In comparison, in non-diabetic patients, risk of intensive care admission increased by 1.7 times for each decrement in standard deviation of anti-SARS-CoV2 antibody levels (OR 1.773, 95%CI 1.377–2.284, p < 0.001). This factor dropped slightly to 1.5 after adjusting for covariates (aOR 1.563, 95%CI 1.177–2.077, p = 0.002). After propensity score matching, the risk of intensive care admission in non-diabetic patients with lower antibody levels increased to 2.8 (aOR 2.827, 95%CI 1.493–5.351, p = 0.001).
We observed significantly higher risks of endotracheal intubation with decreasing anti-SARS-CoV2 antibody levels for the whole study population, as well as in the subgroups of diabetic, non-diabetic and matched, non-diabetic patients before adjusting for potential confounders. However, with the exception of the whole study population (aOR 1.861, 95%CI 1.098–3.155, p = 0.021), these differences did not remain statistically significant after adjusting for age, obesity and SARS-CoV2 variant.
With regard to oxygen administration, patients across all subgroups had significantly higher risk of oxygen administration with decreasing levels of anti-SARS-CoV2 antibody before and after adjusting for potential confounders (whole cohort aOR 1.490, 95%CI 1.279–1.737, p < 0.001; diabetic aOR 1.476, 95%CI 1.111–1.962, p = 0.007; non-diabetic aOR 1.516, 95%CI 1.262–1.822, p < 0.001, non-diabetic, matched aOR 1.456, 95%CI 1.064–1.993, p = 0.019).
Interaction analyses
In order to better understand how anti-SARS-CoV2 antibody levels on hospital admission are affected by the covariates age, SARS-CoV2 variant and obesity we conducted interaction analyses for our primary endpoint, in-hospital mortality, first in the whole cohort, second in diabetic patients and third in non-diabetic patients. There was no significant interaction between anti-SARS-CoV2 antibody levels and SARS-CoV2 variant. We also did not see a significant interaction between obesity and anti-SARS-CoV2 antibody levels.
In contrast, we did see a significant interaction between age and anti-SARS-CoV2 antibody levels across the whole cohort (p = 0.004). With regard to the whole cohort, mean antibody levels showed two peaks, one between 10–20 years of age and another at 70 to 80 years of age, with slightly decreasing means above this age. The lowest mean antibody levels were registered in patients between 40 and 50 years of age. For our type II diabetic patients, we had very few patients aged under 40 years. Above this level, mean antibody levels in diabetic patients peaked at 60–70 years of age.
Mortality rates stratified by renal and cardial markers
Diabetic patients are known to have impaired microcirculation, endothelial dysfunction and reduced respiratory function and are more prone to certain comorbidities including coronary artery disease and renal disease5–7, 10. We therefore aimed to investigate whether mortality rates differed by creatinine and NTproBNP levels in diabetic, non-diabetic and matched, non-diabetic patients.
Patients with elevated levels of creatinine had higher mortality rates than those with normal levels across the whole cohort, non-diabetic and non diabetic matched patients (14.9% vs. 5.4%, p < 0.001; 12.8% vs. 4.4%, p < 0.001; 16.8% vs. 7.9%, p = 0.045). Comparable results were observed for patients with elevated levels of NTproBNP (12.5% vs. 2.3%, p < 0.001; 10.4% vs. 1.6%, p < 0.001; 15.4 vs. 0%, p = 0.005). In diabetic patients, there was a trend towards higher mortality rates in patients with elevated creatinine (19.0% vs. 10.9%) or NTproBNP levels (18.0% vs. 6.8%) compared to patients with normal levels that did not reach statistical significance.
Among patients with elevated levels of NTproBNP, diabetic patients had higher mortality rates than non-diabetic patients (18.0% vs. 10.4%, p = 0.005). In comparison to matched, non-diabetic patients, diabetic patients still had slightly higher mortality rates, although no longer statistically significant (18.0% vs. 15.4%, p = 0.507). In patients with elevated levels of NTproBNP, anti-SARS-CoV2 spike antibodies were significantly lower in non-survivors than in survivors (mean 356U/ml, 95%CI 185–528 vs. 1045U/ml, 95%CI 955–1136, p < 0.001).
Among patients with elevated levels of creatinine, there was no statistically significant difference in mortality between diabetic and non-diabetic patients. Low anti-SARS-CoV2 spike antibodies continued to be strongly associated with higher in-hospital mortality in patients with elevated creatinine levels (mean 342U/ml, 95%CI 143–241 vs. 1050U/ml, 95%CI 935–1164, p < 0.001).