Chung, S-C

Providencia, R

Sofat, R

English

UCL Discovery

C o r r e s p o n d e n c eT h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med nejm.org 1Association between Angiotensin Blockade  and Incidence of Influenza in the United KingdomTo the Editor: Some researchers have hypoth-esized that drugs that interfere with the renin–angiotensin–aldosterone system (RAAS), including angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), may in-crease susceptibility to coronaviruses. This hypoth-esis is based on the observation that coronavi-ruses engage ACE2 for cell entry1 and that altered expression of ACE2 is influenced by the use of ACE inhibitors and ARBs, an action that has been shown in animal models.2 Influenza A (H7N9, H1N1, and H5N1) has been shown to use the ACE2 receptor to mediate lung damage, similar to that seen in severe acute respiratory syndrome (SARS).3 Understanding the shared mechanism between SARS and influenza may help to address the question as to how ACE inhibitors and ARBs may modulate the manifestations of certain viral respiratory infections.In this study, we used the linked electronic health care records of 5.6 million persons in the United Kingdom from the Clinical Practice Re-search Datalink (CPRD)4 to investigate the inci-dence of influenza among adults (≥18 years of age) who had received a prescription for an ACE inhibitor from 1998 through 2016. Permission for the use of CPRD and Hospital Episode Statis-tics (HES) data for the research was provided by the CPRD independent scientific advisory com-mittee. We defined exposure to an ACE inhibitor as a documented prescription during the study period. We performed additional analyses to assess the association between the incidence of influ-enza and the duration of use of an ACE inhibitor, which was defined as the sum of prescription days (categorized as none, <0.5 years, 0.5 to <1.5 years, 1.5 to <2.5 years, 2.5 to <3.5 years, 3.5 to <5.0 years, 5.0 to <7.5 years, 7.5 to <10.0 years, and ≥10.0 years). The same methods were used to assess the association between the use of ARBs and the incidence of influenza.We identified 700,994 persons who had received a prescription for an ACE inhibitor and 230,028 who had received a prescription for an ARB. A to-tal of 4,742,017 persons in the database had not received a prescription for an ACE inhibitor, an ARB, or the direct renin inhibitor aliskiren. Defi-nitions of influenza were drawn from the Global Burden of Disease Study 2017,5 including codes J09 through J11.8 of the International Statistical Classi-fication of Diseases, 10th Revision. (Details are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) Analyses were adjusted for age at baseline, sex, smoking history, presence of obesity, influenza vaccination, the presence of 12 coexisting conditions (diabetes, hypertension, stable angina, ischemic heart dis-ease, atrial fibrillation, stroke, asthma, cancer, chronic obstructive pulmonary disease, chronic kidney disease, heart failure, and dementia), and the time period of the influenza outbreak.During a median 8.7 years of follow-up, per-sons who had received a prescription for an ACE inhibitor had a lower risk of influenza than those who had not (adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.62 to 0.70) (Fig. 1A and 1C). A curvilinear relationship was observed be-tween the number of prescription days and inci-dent influenza. As compared with no prescrip-tion days, the hazard ratio for incident influenza was 0.99 (95% CI, 0.91 to 1.07) for a duration of less than 0.5 years, 0.74 (95% CI, 0.65 to 0.85) for a duration of 2.5 to less than 3.5 years, and 0.52 (95% CI, 0.46 to 0.58) for a duration of 5.0 to less than 7.5 years. Analyses comparing the inci-dence of influenza and the use of ARBs showed results that were similar to the findings with ACE inhibitors (Fig. 1B and 1D).Thus, the use of ACE inhibitors and ARBs was associated with either no effect on the incidence of influenza or a lower incidence, depending on the duration of use. These associations regarding The New England Journal of Medicine Downloaded from nejm.org on May 13, 2020. For personal use only. No other uses without permission.  Copyright © 2020 Massachusetts Medical Society. All rights reserved. T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med nejm.org 2Incidence of Influenza (%)1.00.60.80.90.50.40.20.10.30.70.0056432178910Years of Follow-upCAnalyses of ACE Inhibitors (N=5,443,011)AIncidence of Influenza, According to Use of ACE Inhibitors No. at RiskNo ACEI useACEI use4,742,017700,9944,121,721543,1373,621,054419,5533,151,276313,5002,687,129221,1712,239,977140,567No ACEI useACEI useIncidence of Influenza (%)1.00.60.80.90.50.40.20.10.30.00.0056432178910Years of Follow-upBIncidence of Influenza, According to Use of ARBsNo. at RiskNo ARB useARB use4,734,983230,0284,114,907177,4833,614,448135,6563,144,872100,3242,680,84668,7992,233,93140,905No ARB useARB use0.51.00.81.2No ACE Inhibitor BetterACE Inhibitor BetterAny ACEI useNone<0.5 Yr0.5 to <1.5 Yr1.5 to <2.5 Yr2.5 to <3.5 Yr3.5 to <5.0 Yr5.0 to <7.5 Yr7.5 to <10.0 Yr≥10 YrAdjusted Hazard Ratio for Incidence of Influenza (95% CI)Category of Use0.29 (0.26–0.32)0.66 (0.58–0.74)0.52 (0.46–0.58)0.35 (0.30–0.40)0.74 (0.65–0.85)0.89 (0.80–1.00)1.07 (0.97–1.17)0.66 (0.62–0.70)0.20.99 (0.91–1.07)ReferenceDAnalyses of ARBs (N=4,965,011)0.51.00.81.2No ARB BetterARB BetterAny ARB useNone<0.5 Yr0.5 to <1.5 Yr1.5 to <2.5 Yr2.5 to <3.5 Yr3.5 to <5.0 Yr5.0 to <7.5 Yr7.5 to <10.0 Yr≥10 YrAdjusted Hazard Ratio for Incidence of Influenza (95% CI)Category of Use0.11 (0.08–0.15)0.51 (0.42–0.62)0.45 (0.38–0.54)0.19 (0.15–0.26)0.60 (0.48–0.75)0.88 (0.73–1.06)1.15 (0.98–1.35)0.52 (0.47–0.57)0.20.96 (0.83–1.12)ReferenceThe New England Journal of Medicine Downloaded from nejm.org on May 13, 2020. For personal use only. No other uses without permission.  Copyright © 2020 Massachusetts Medical Society. All rights reserved. Correspondencen engl j med nejm.org 3observed susceptibility to influenza may reflect mechanisms that are shared with coronaviruses, including SARS-CoV-2.Sheng‑Chia Chung, Ph.D.University College London London, United Kingdom s . chung@ ucl . ac . ukRui Providencia, M.D., Ph.D.Barts Health NHS Trust London, United KingdomReecha Sofat, M.D., Ph.D.University College London London, United Kingdom r . sofat@ ucl . ac . ukDisclosure forms provided by the authors are available with the full text of this letter at NEJM.org.This letter was published on May 8, 2020, at NEJM.org.1. Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270-3.2. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angioten-sin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circula-tion 2005; 111: 2605-10.3. Yang P, Gu H, Zhao Z, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung in-jury. Sci Rep 2014; 4: 7027.4. Denaxas S, Gonzalez-Izquierdo A, Direk K, et al. UK phe-nomics platform for developing and validating electronic health record phenotypes: CALIBER. J Am Med Inform Assoc 2019; 26: 1545-59.5. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analy-sis for the Global Burden of Disease Study 2017. Lancet 2018; 392: 1736-88.DOI: 10.1056/NEJMc2005396Correspondence Copyright © 2020 Massachusetts Medical Society.Figure 1 (facing page). Adjusted Kaplan–Meier Analyses and Hazard Ratios for Incident Influenza, According to Duration of Use of ACE Inhibitors and ARBs.Shown is the incidence of influenza according to the use of an angiotensin‑converting–enzyme inhibitor (ACEI) (Panel A) or angiotensin‑receptor blocker (ARB) (Panel B). Also shown are hazard ratios for in‑fluenza in subgroups of persons who received a pre‑scription for an ACE inhibitor (Panel C) or ARB (Panel D), according to the duration of use. All analyses have been adjusted for the age at baseline, sex, smoking history, presence of obesity, influenza vaccination, the presence of 12 coexisting conditions, and the time pe‑riod of the influenza outbreak.The New England Journal of Medicine Downloaded from nejm.org on May 13, 2020. For personal use only. No other uses without permission.  Copyright © 2020 Massachusetts Medical Society. All rights reserved. 

Association between Angiotensin Blockade and Incidence of Influenza in the United Kingdom

https://discovery.ucl.ac.uk/10097387/1/nejmc2005396.pdf

Association between Angiotensin Blockade and Incidence of Influenza in the United Kingdom

Abstract

Similar works

Full text

Available Versions

UCL Discovery