key: cord-0982797-2vbv0pj7 authors: Dalan, Rinkoo; Ang, Li Wei; Tan, Wilnard Y T; Fong, Siew-Wai; Tay, Woo Chiao; Chan, Yi-Hao; Renia, Laurent; Ng, Lisa F P; Lye, David Chien; Chew, Daniel E K; Young, Barnaby E title: The association of hypertension and diabetes pharmacotherapy with COVID-19 severity and immune signatures: an observational study date: 2020-08-07 journal: Eur Heart J Cardiovasc Pharmacother DOI: 10.1093/ehjcvp/pvaa098 sha: 8b96597cd2d9a533bddc21786d8d27f921ff3cac doc_id: 982797 cord_uid: 2vbv0pj7 nan Coronavirus disease 2019 in patients with co-existing diabetes and hypertension is associated with an increased risk of severe infections and mortality (1) . There is a paucity of data on the association of pharmacotherapy of these conditions with COVID-19 disease severity. We conducted a retrospective, observational cohort study of 717 patients with PCR-confirmed COVID-19 who were hospitalised at the National Centre of Infectious diseases (NCID), Singapore up to April 15, 2020. Data collected included demographics, co-morbidities, concomitant medications, and clinical outcomes. Primary outcomes were hypoxia (requirement for supplemental oxygen to maintain blood oxygen saturations >93%), intensive care unit (ICU) admission, mechanical ventilation or death. The study was conducted in accordance with institutional guidelines; study protocols were reviewed and approved, by the Ministry of We used the modified Poisson regression approach (2) to calculate the relative risk (RR) for the association between requirement for supplementary oxygen, ICU admission, mechanical ventilation, and death with diabetes, hypertension and pharmaco-therapeutics. RR was adjusted for demographics, comorbidities and co-medications. Multivariable linear regression models were used to assess the association between inflammatory markers, and the use of medications. All statistical tests were two-sided, and statistical significance was taken as p<0.05. All statistical analyses were performed using Stata version 15. Cytokine levels across groups were compared using two-tailed Mann Whitney U test. . In the diabetes subgroup, patients receiving a DPP4i were at higher risk of ICU admission (aRR 4.07, 95% CI 1.42-11.66) ( Table 1 ). SGLT2i was associated with a marginally lower risk of mechanical ventilation (aRR 0.03, 95% CI 0.00-0.70). Sensitivity analysis adjusting for BMI, HbA1c, systolic and diastolic blood pressure at baseline showed similar results ( Table 1 ). The results also remained materially unchanged when the analysis was confined to patients on metformin. Since 88% of patient with diabetes received metformin it was not possible to analyse its effects. In the hypertension subgroup, the use of ARB was associated with higher C-reactive protein concentrations (-19.0; p=0.038), white blood cell counts (-1.14, p=0.006) and neutrophil counts (-1.24, p=0.002) when adjusted for age, gender and ethnicity. Diabetes patients on DPP4i had significantly lower brain derived neurotrophic factor (BDNF). Hypertension patients on ARB treatment had significantly higher MCP-1 and IP-10 concentrations compared to non-ARB users. (Figure 1 ). Longitudinal profiling of these cytokines showed that IFN-, IL-18, IL-15 and BDNF trends were mixed during disease progression in diabetes patients with no differences with treatment whilst MCP-1 and IP-10 concentrations continued to remain significantly higher in hypertension ARB users vs non-users. We found that patients with COVID-19 and diabetes or hypertension had more severe infections with a higher requirement for oxygen and ICU admission. These results are similar to other larger observational studies reported globally (1). As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the angiotensin converting enzyme -2 (ACE-2) for entry into alveolar cells (3), there has been concern about the effect of RAS modulators on COVID-19 severity. The concerns about possible increased viral transmission due to upregulation of the ACE-2 enzyme expression has been recently debunked as a large population-based study showed no correlation with viral transmission (4, 5) . In the hypertension cohort, ACE-I was associated with better outcomes. In a recent metaanalysis, which included 16 studies involving 24,676 patients, they similarly found that the use of ACE-I associated with better disease outcomes (6) . Conflicting results have been reported from various centers as highlighted in another meta-analysis (7). Many studies have combined ACE-I and ARBs into one group as they have patients on a combination and thus, they are unable to study the effects individually. Our cohort did not have a single patient who were taking both ACE-I and ARB allowing us to individually assess these medications. Since ACE-I blocks the formation of angiotensin-II completely, it can lead to a counter upregulation of the ACE-2 pathway which can protect against respiratory failure (8). On the other hand, ARB blocks the AT1R with a concomitant increase in angiotensin-II. Angiotensin-II can act through other receptors like (AT3R and AT4R) which are not completely blocked by ARBs (9). Serum angiotensin-II concentrations have been seen to correlate with viral load and lung injury in COVID-19 (10). Moreover, angiotensin-II can induce endothelial cell synthesis of MCP-1 and IP-10 , pro-inflammatory cytokines which has been identified to be strongly associated with severe COVID-19 (10, 11) . This is consistent with our observations that the patients receiving ARB treatment have higher levels of plasma MCP-1 and IP-10 compared to patients receiving ACE-I treatment, or neither. In the diabetes cohort, we found that patients on DPP4-inhibitors were more likely to require ICU admission. In COVID-19, the adaptive T-cell immune response is thought to play a significant role in determining disease severity. If the T-cell and B-cell response are not effective, immune cells accumulate in the lungs, causing overproduction of pro-inflammatory 6 cytokines and damaging inflammation (12) . DPP4 inhibitors have been associated with the suppression of T cell proliferation response which may result in a less effective immune response to the virus (13) . In support of this hypothesis, we did observe a significant decrease in brain derived neurotrophic factor (BDNF), which is important for T-cell maturation ( Figure 1 ). In BDNF knockout mice and in conditional knockout mice lacking BDNF (specifically in this lymphoid subset), diminished T-cell cellularity in peripheral lymphoid organs has been demonstrated suggestive of a critical paracrine and autocrine role in thymocyte development (14) . This study is limited by its single center design, observational study design and relatively small sample size. We found a beneficial signal for ACE-I and a deleterious signal for ARB and DPP4-inihibitors with evidence of deleterious immune signatures. Data from larger observational cohorts and ongoing randomized controlled trials is urgently needed to confirm or refute these findings. 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