Nicotine-replacement therapy, as a surrogate of smoking, and the risk of hospitalization with Covid-19 and all-cause mortality: a nationwide, observational cohort study in France

Abstract

Introduction Several studies have reported an unexpectedly low prevalence of current smoking among hospitalized patients with Covid-19. However, these studies mostly compared observed to expected rates of smoking without direct comparison with individual controls. Objective To examine the association of nicotine-replacement therapy, as a surrogate of smoking, with hospitalization and all-cause mortality during the first wave of SARS-CoV-2 epidemic in France. Methods We conducted a nationwide matched exposed/unexposed cohort study using information from the French national health data system which covers the entire French population. We conducted two separate analyses, the first in individuals exposed to nicotine-replacement therapy without major smoking-related diseases (cancer, cardiovascular and/or respiratory diseases) and the second in those presenting these conditions. We included all individuals, aged between 18 and 75 years, who had been reimbursed at least one nicotine-replacement therapy between November 15, 2019, and February 15, 2020. For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). The three end points were a hospitalization with Covid-19, a death or an intubation in hospitalized patients with Covid-19, and all-cause mortality. We compared outcomes in individuals who were exposed to nicotine-replacement therapy with those in individuals who were not, using a multivariable Cox model with inverse probability weighting according to the propensity score. Results In the first analysis, 297,070 individuals without major smoking-related diseases exposed to nicotine-replacement therapy were matched with 558,228 unexposed individuals without major smoking-related diseases. Individuals were aged on average 45.6 years (standard deviation: 12.7) and 48.8% were male. From February 15, 2020 to June 7, 2020, hospitalization with Covid-19 occurred in 647 patients (151 patients in the nicotine-replacement therapy group and 496 patients in the unexposed group). In the main multivariable analysis, nicotine-replacement therapy was associated with a decreased risk of hospitalization with Covid-19 compared with unexposed individuals (hazard ratio, 0.50; 95% CI, 0.41 to 0.61). Nicotine-replacement therapy exposure was also associated with a decreased risk of intubation or death in hospitalized individuals with Covid-19 (13 vs. 73 patients, hazard ratio, 0.31; 95% CI, 0.17 to 0.57) but with an increased risk of all-cause mortality (251 vs. 231 deaths, hazard ratio, 1.49; 95% CI, 1.24 to 1.80). In the second analysis, 128,768 individuals with major smoking-related diseases exposed to nicotine-replacement therapy were matched with 243,793 unexposed individuals. Individuals were aged on average 55.3 years (standard deviation: 11.4) and 53.3% were male. In the main multivariable analysis, nicotine-replacement therapy exposure was neither associated with risk of hospitalization with Covid-19 (240 patients in the nicotine-replacement therapy group and 398 patients in the unexposed group, hazard ratio, 1.13; 95% CI, 0.94 to 1.38) nor with risk of death or an intubation in hospitalized individuals with Covid-19 (48 vs. 61 patients, hazard ratio, 1.00; 95% CI, 0.65 to 1.54). All-cause mortality was higher in the nicotine-replacement therapy group (1040 vs. 366 deaths, hazard ratio, 3.83; 95% CI, 3.41 to 4.31). Conclusions This large-scale observational study suggests that smoking, measured by exposure to nicotine-replacement therapy, was associated with an increased risk of overall mortality during the first wave of SARS-CoV-2 epidemic in France, although it was associated with a lower risk of severe Covid-19 in individuals without major related-smoking diseases. Experimental and clinical studies are needed to disentangle the potential mechanisms of nicotine and/or smoking in Covid-19 risk. Whatever the nature of these associations, the global impact of smoking is harmful for health even over a short epidemic period.

Nicotine upregulates ACE2 expression and increases competence for SARS-CoV-2 in human pneumocytes

“…Evidence from these studies is somehow contrasting, and the role of tobacco smoking, NRT, or vaping is still to be assessed [4][5][6][7][50][51][52][53][54][55][56][57]. In many cases, the presence of underreporting in recording smoking history at admission, especially to ICU during the COVID-19 outbreak, when the hospitals are overwhelmed, cannot be ruled out.…”

Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

“…In fact, based on these findings, an acetylcholinesterase inhibitor 124, 125 and a nicotinic receptor agonist have been tested 126, 127 . However, recent studies have demonstrated that nicotine and smoking increase ACE2 receptor density 128, 129 , and that the potential beneficial effects of nicotine were restricted to a small group of individuals 130 . Our findings provide a warning that precautions should be taken when considering the therapeutic use of nicotinic agonists, since patients with severe/critical Covid-19 were found to release high amounts of ACh, in addition to showing increased levels of M3-receptor expression.…”

Chronic diseases, health conditions and risk of COVID-19-related hospitalization and in-hospital mortality during the first wave of the epidemic in France: a cohort study of 66 million people

“…We conducted a cohort study on the National Health Data System (SNDS) that covers the entire French population, i.e. 67 million inhabitants, and which has been extensively used in France to conduct pharmaco-epidemiology studies [ [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] ] including studies on the COVID-19 pandemic.…”