COVID-19 and the nicotinic cholinergic system.

To the Editor:

We have read with great interest the paper by Leung et al. [1] published in the European Respiratory Journal, the correspondence by Russo et al. [2], and also the subsequent comment by the first group [3]. Both research teams are reporting increased angiotensin-converting enzyme 2 (ACE-2) expression in airways of current smokers and those with COPD, with important implications for coronavirus disease 2019 (COVID-19) patients. Since ACE-2 has been shown to be the main receptor utilised by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter the host cells [2], the authors conclude that nicotine is a risk factor for COVID-19. Russo et al. [2] have shown that nicotine upregulates ACE-2 through α7-nAChRs which are present in neuronal and non-neuronal cells. Leung et al. [3] provided further evidence in support of this hypothesis and propose the repurposing of α7-nAChR antagonists for the pandemic (e.g. methyllycaconitine, α-conotoxin), expecting that such treatment will alter ACE-2 expression and prevent SARS-CoV-2 entry.

While this hypothesis is based on laboratory experiments, it is not supported by clinical data. Recent observations on the prevalence of smoking among hospitalised COVID-19 patients have raised some important issues. Many studies, while based on preliminary data and subject to several limitations (e.g. lack of adjustment for confounding factors, possibility for inability to report, inaccurate recording or under-reporting of the smoking status), suggest that the proportion of hospitalised COVID-19 patients who are current smokers is by far lower than expected based on population smoking rates [4, 5]. In one study, smoking was associated with lower odds of hospitalisation for COVID-19 after adjusting for covariates [6].

To further address this issue, we calculated the pooled prevalence of current smoking in 11 published case series (table 1), nine from China and two from the USA [5-15], and compared it to the expected prevalence based on gender-adjusted and gender- and age-adjusted population smoking rates in each country by estimating the prevalence odds ratio (POR) using random effects meta-analysis. Due to the lack of data on patients’ age distribution, the age-adjustment for the expected smoking prevalence was calculated by assuming that all patients were aged ≥65 years, since lower smoking prevalence is observed in the elderly compared to younger adult age groups. Population smoking prevalence information was derived from the World Health Organization 2018 Global Adult Tobacco Survey [16] for China, and from the US Centers for Disease Control and Prevention (for gender adjustment) [17] and Statista (for gender and age adjustment) [18]. The pooled prevalence of smoking was 5.3% (95% CI 3.2–8.0%), while the gender adjusted POR was 0.16 (95% CI 0.12–0.23; p<0.001) and the gender- and age-adjusted POR was 0.20 (95% CI 0.14–0.30; p<0.001). Despite the many limitations, these observations need to be taken into consideration. Recently, a hypothesis that the nicotinic cholinergic system may be involved in COVID-19 infection was presented, based on the fact that several of the symptoms and clinical signs of COVID-19, including the cytokine storm, could be explained by dysfunction of the cholinergic anti-inflammatory pathway [19]. α7-nAChRs are potentially involved in modulating pro-inflammatory cytokine secretion and suppressing the cytokine storm [20, 21]. Additional clinical manifestations of COVID-19 (such as anosmia and thromboembolic complications) can also be associated with dysfunction of the nicotinic cholinergic system [19].

TABLE 1

Studies used to estimate the pooled prevalence and the prevalence odds ratio of current smoking among hospitalised coronavirus disease 2019 patients

	Country	Patients n	Age	Males %	Females %	Smokers n	Smokers % (95% CI)	Expected smokers %		Prevalence odds ratio (95% CI)
								Gender-adjusted	Gender and age-adjusted¶	Gender-adjusted	Gender and age-adjusted¶
CDC [5]#	USA	1494				27	1.8 (1.2–2.6)	13.7%	8.8%	0.12 (0.08–0.17)	0.19 (0.13–0.29)
Guanet al. [7]	China	1085	47 (35–58)	58.1%	41.9%	137	12.6 (10.6–14.6)	30.2%	27.3%	0.36 (0.28–0.44)	0.39 (0.31–0.48)
Chenet al. [8]	China	274	62 (44–70)	62.4%	37.6%	12	5.4 (2.4–8.3)	32.3%	29.0%	0.10 (0.05–0.19)	0.11 (0.06–0.21)
Zhouet al. [9]	China	191	56 (46–67)	62.3%	37.7%	11	5.8 (2.5–9.1)	32.3%	29.0%	0.14 (0.07–0.27)	0.15 (0.08–0.30)
Moet al. [10]	China	155	54 (42–66)	55.5%	44.5%	6	3.9 (0.9–6.9)	29.0%	26.2%	0.11 (0.04–0.26)	0.11 (0.05–0.28)
Zhanget al. [11]	China	140	57 (25–87)	50.7%	49.3%	2	1.4 (0.0–3.3)	26.6%	24.3%	0.04 (0.01–0.18)	0.05 (0.01–0.19)
Wanet al. [12]	China	135	47 (36–55)	53.3%	46.7%	9	6.7 (2.5–10.9)	27.9%	25.4%	0.20 (0.09–0.43)	0.21 (0.10–0.46)
Liuet al. [13]	China	78	38 (33–57)	50.0%	50.0%	5	6.4 (0.1–11.8)	26.3%	24.1%	0.20 (0.07–0.58)	0.22 (0.08–0.61)
Huanget al. [14]	China	41	49 (41–58)	73.2%	26.8%	3	7.3 (0.0–15.3)	37.5%	33.3%	0.14 (0.04–0.54)	0.16 (0.04–0.61)
Zhanget al. [15]	China	645	35±14.247±14	50.9%	49.1%	41	6.4 (4.6–8.5)	26.7%	24.4%	0.20 (0.14–0.28)	0.21 (0.15–0.30)
Petrilliet al. [6]	USA	1999	62 (50–74)	62.6%	37.4%	104	5.1 (4.2–6.1)	14.0%	9.2%	0.33 (0.26–0.42)	0.54 (0.42–0.69)
Total (pooled)		4743				330	5.3 (3.2–8.0)			0.16 (0.12–0.23)	0.20 (0.14–0.30)

Random-effects meta-analysis was used. Data for age are presented as median (interquartile range) or mean±sd. Data on population smoking prevalence were derived from the World Health Organization 2018 Global Adult Tobacco Survey for China, and from the US Centers for Disease Control and Prevention for gender-specific smoking prevalence and Statista for gender specific smoking prevalence in adults aged ≥65 years for the USA. #: no data about patients’ age and gender was available; thus, the unadjusted population prevalence of smoking in the USA was used to calculate the expected number of smokers; ¶: since the age distribution of patients was not available, age-adjusted smoking prevalence was calculated for all studies by assuming that all patients were aged ≥65 years.

In conclusion, the observations of a low smoking prevalence among hospitalised COVID-19 patients, despite the important limitations, together with the hypothetical links between dysfunction of the nicotinic cholinergic system and clinical manifestations of the disease raise some important research questions, considering that nicotine is a cholinergic agonist. The interaction between SARS-CoV-2 and the nicotinic cholinergic system should be further examined and any proposal for the repurposing of α7-nAChR antagonists should be approached with caution, since it could potentially propagate the cytokine storm and adversely affect the prognosis. Obviously, smoking cannot be considered protective for COVID-19 (or any other disease), but pharmaceutical nicotine products are widely available and their role in COVID-19 should be explored.

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