Low incidence of daily active tobacco smoking in patients with symptomatic COVID-19

Importance: As the pandemic of COVID-19 is still under progression, identification of prognostic factors remains a global challenge. T he role of cigarette smoking has been suggested among the disease’s epidemiological risk factors, although it is highly controversial. Objective: T o evaluate the correlation of daily smoking with the susceptibility to develop SARS-CoV-2 infection. Participants: We estimated the rates of daily current smokers in COVID-19-infected patients in a large French university hospital between February 28th , 2020 and March 30th , 2020 for outpatients and from March 23rd , till April 9th , 2020 for inpatients. Design: T he rates from both groups were compared to those of daily current smokers in the 2018 French general population, established in 2018, after standardization of the data for sex and age. Results: T he inpatient group was composed of 343 patients, median age 65 yr: 206 men (601%, median age 66 years) and 137 women (39.9%, median age 65 years) with a rate of daily smokers of 4.4% (5.4% of men and 2.9% of women).T he outpatient group was composed of 139 patients, median age 44 years: 62 men (44.6 %, median age 43 years, and 77 women (55.4 %, median age 44 years). T he daily smokers rate was 5.3% (5.1% of men and 5.5 % of women). In the French population, the daily smokers rate was 25.4% (28.2% of men and 22.9% of women). T he rate of current daily smokers was significantly lower in COVID-19 outpatients and inpatients (80.3% and 75.4%, respectively), as compared to that in the French general population with standardized incidence ratios according to sex and age of 0.197 [0.094 Qeios, CC-BY 4.0 · Article, April 21, 2020 Qeios ID: WPP19W.3 · https://doi.org/10.32388/WPP19W.3 1/13 0.41] and 0.246 [0.148 0.408]. T hese ratios did not significantly differ between the two groups (P=0.63). Conclusions and relevance: Our cross sectional study in both COVID-19 outand inpatients strongly suggests that daily smokers have a very much lower probability of developing symptomatic or severe SARS-CoV-2 infection as compared to the general population. Introduction As the pandemic of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still under progression, the identification of prognostic factors is a global challenge. Among epidemiological risk factors, the role of smoking, to date, is unclear. Smoking has been initially found associated with adverse disease prognosis of COVID19[1], although this finding remains controversial[2]. Reported rates of current smokers among SARS-CoV-2-infected patients are heterogeneous, ranging from 1.4% to 12.5% (T ABLE [1, 3-10]). T he rates of current smokers remain however strikingly low for the middle-aged Chinese population (median age: 47.0 years; range: 35.0–58.0; in Guan et al.[1]). T hese data notwithstanding, no firm conclusions can be drawn from the available COVID-19 studies because main potential confounders, like age and sex, were not taken into account. Additionally, these studies included mostly hospitalized patients, and the low rate of current smokers may be related to high rate of patients with comorbidities (smokers having been advised to quit) and thus to COVID-19 severity. T his could therefore introduce a confusion bias. T o allow for a valid comparison with the general population, smoking rates used as a reference should have been evaluated at a time as close as possible to the time of COVID pandemic and the same definitions of current smokers should be used for both COVID-19 and general populations, which was not clear in the previous studies. T he last available study of the Chinese general population in 2015 reported rates of current smokers of 52% for men and 2.5 % for women[11]. Very recently, the US Center of Disease Control reported an analysis of current smoker rate among US COVID-19 patients which was found to be 1.3% for the whole population of COVID-19 patients, 1% for outpatients, 2% for patients, not hospitalized in an ICU, and 1% in intensive care unit (ICU)-admitted patients[12]. However, the level of missing smoking status was very high and no comparison with the general population was performed. Qeios, CC-BY 4.0 · Article, April 21, 2020 Qeios ID: WPP19W.3 · https://doi.org/10.32388/WPP19W.3 2/13 TABLE 1 Prevalence of smokers in COVID-19 patients in published series T herefore, the hypothetic « protective » effect of current smoking on the risk of SARSCoV-2 infection that can be extrapolated from the low current smoker rate has yet to be determined. T o accurately evaluate whether or not current smoking is associated with the risk of contracting a symptomatic SARS-CoV-2 infection, we compared the rates of current smokers after standardization by sex and age of two COVID-19 patients’ groups, one composed of outpatients (not subsequently hospitalized) and one of hospitalized patients (inpatients) with those reported in the 2018 French general population[13]. Mat er i a l an d met h ods Pat i en t s an d desi g n T his is a cross-sectional survey investigating the rate of current smokers in patients with a diagnosis of COVID-19, both in hospitalized patients (representing the severe symptomatic cases of COVID-19) and in outpatients (i.e. patients who represent the nonsevere symptomatic cases of this infection). Current smoker rates were compared to those of the French population as a reference, after standardization by age and sex. Eligible patients were those with a confirmed diagnosis of COVID-19 at the APHP PitiéSalpêtrière Hospital, Paris, France, either hospitalized in medical wards of medicine, but not in ICUs (inpatients) or having consulted for this infection in the infectious disease department and who did not require hospital care until the end of the acute infectious Qeios, CC-BY 4.0 · Article, April 21, 2020 Qeios ID: WPP19W.3 · https://doi.org/10.32388/WPP19W.3 3/13 episode (outpatients). Data from inpatients, hospitalized from March 23 to April 9, 2020 and from outpatients, who consulted from February 28 to March 30, 2020 were collected. T his study is observational. All data were collected in the context of care and in completely anonymous sheets and therefore, in accordance with the French law, including the General Data Protection Regulation (GDPR), informed consent of the patient was not sought. T he study has been approved by the ethics committee of Sorbonne University (2020 CER-2020-13). Definit ions and data collected Confirmed COVID-19 was defined as a positive result on real-time reverse-transcriptase– polymerase-chain-reaction (RT -PCR) assay of nasal and pharyngeal swab specimens. Smoking status was collected and patients were specifically asked whether they were current smokers (and if so, to provide details on their smoking habits: daily or occasional smoking, type of tobacco products used, number of daily cigarettes), former smokers, or not smokers ever). Daily smokers are individuals reporting daily smoking or reporting a daily frequency of the number of cigarettes (manufactured or rolled) or other tobacco products (cigars, cigarillos, pipe, shisha)13. Occasional smokers are individuals reporting infrequent, but not daily smoking. T he group of ex-smokers included anyone having smoked in the past, occasionally or daily, and had abstained from smoking prior to the time of investigation. T he term "never smoker" designated people who had never smoked. T he quantities of tobacco smoked were calculated using the following equivalences: 1 cigar = 1 cigarillo = 2 cigarettes. In addition to smoking status, the following data were extracted from the medical charts: age, sex, comorbidities, known to have potentially an impact on the prognosis of COVID19, including diabetes, hypertension, obesity, immunodepression and respiratory disease (such as COPD, other clinical manifestations of COVID-19 and outor inpatient status. Sm ok i ng r at e i n t he p op ul at i on of r ef er enc e T he French general population was used as a reference to compute the Standardized Incidence Ratio (SIR). Recent rates of current daily smokers have been reported for the year 2018 by sex and age class (of 10 years) from the General Survey “Baromètre de Santé Publique France” of the French population, cross sectional phone survey made yearly on a representative sample of 18-75 year-old people living in mainland France, with a on 2-level random sampling[13]. T he 2018 survey involved a sample of 9,074 individuals. T he completion of the survey took place from January 10 to July 25, 2018 and used the same definitions of daily smokers, occasional smokers, former smokers and Qeios, CC-BY 4.0 · Article, April 21, 2020 Qeios ID: WPP19W.3 · https://doi.org/10.32388/WPP19W.3 4/13 never smokers as described above. St at i s t i c a l anal ys i s A descriptive analysis has been made by group (inpatients outpatients). Qualitative variables were described by numbers and percentages, and quantitative variables by median and interquartile range. Inpatients and outpatients were compared for qualitative variables with Pearson Chi2 tests or Fisher’s exact test as appropriate and for quantitative variables with Wilcoxon sum rank test. T he SIRs were used to compare current daily smoker rates in the COVID-19 inpatients and outpatients, respectively, with those of current daily smokers in a reference population, here the French general population in 2018. T he estimated SIR and its 95% confidence interval is the ratio between the observed number of current daily smokers among the COVID-19 patients and the number of current daily smokers that would be expected, on the basis of ageand genderspecific current daily smokers rates in the general population. T he main analysis involved all included patients, and those older than 75 years were considered in the 65-75 years age class for standardization, which for our hypothesis is a conservative approach, because current smoker rates decreases with age. For 7 outpatients


Introduction
As the pandemic of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still under progression, the identification of prognostic factors is a global challenge. Among epidemiological risk factors, the role of smoking, to date, is unclear. Smoking has been initially found associated with adverse disease prognosis of COVID-19 [1], although this finding remains controversial [2]. Reported rates of current smokers among SARS-CoV-2-infected patients are heterogeneous, ranging from 1.4% to 12.5% (T ABLE [1,[3][4][5][6][7][8][9][10]). T he rates of current smokers remain however strikingly low for the middle-aged Chinese population (median age: 47.0 years; range: 35.0-58.0; in Guan et al. [1]). T hese data notwithstanding, no firm conclusions can be drawn from the available COVID-19 studies because main potential confounders, like age and sex, were not taken into account. Additionally, these studies included mostly hospitalized patients, and the low rate of current smokers may be related to high rate of patients with comorbidities (smokers having been advised to quit) and thus to COVID-19 severity. T his could therefore introduce a confusion bias. T o allow for a valid comparison with the general population, smoking rates used as a reference should have been evaluated at a time as close as possible to the time of COVID pandemic and the same definitions of current smokers should be used for both COVID-19 and general populations, which was not clear in the previous studies. T he last available study of the Chinese general population in 2015 reported rates of current smokers of 52% for men and 2.5 % for women [11]. Very recently, the US Center of Disease Control reported an analysis of current smoker rate among US COVID-19 patients which was found to be 1.3% for the whole population of COVID-19 patients, 1% for outpatients, 2% for patients, not hospitalized in an ICU, and 1% in intensive care unit (ICU)-admitted patients [12].
However, the level of missing smoking status was very high and no comparison with the general population was performed.  M a t e r i a l a n d m e t h od s P a t i e n t s a n d d e si g n M a t e r i a l a n d m e t h od s P a t i e n t s a n d d e si g n T his study is observational. All data were collected in the context of care and in completely anonymous sheets and therefore, in accordance with the French law, including the General Data Protection Regulation (GDPR), informed consent of the patient was not sought. T he study has been approved by the ethics committee of Sorbonne University (2020 -CER-2020-13).

Definitions and data collected
Confirmed COVID-19 was defined as a positive result on real-time reverse-transcriptasepolymerase-chain-reaction (RT -PCR) assay of nasal and pharyngeal swab specimens.
Smoking status was collected and patients were specifically asked whether they were current smokers (and if so, to provide details on their smoking habits: daily or occasional smoking, type of tobacco products used, number of daily cigarettes), former smokers, or not smokers ever). Daily smokers are individuals reporting daily smoking or reporting a daily frequency of the number of cigarettes (manufactured or rolled) or other tobacco products (cigars, cigarillos, pipe, shisha)13. Occasional smokers are individuals reporting infrequent, but not daily smoking. T he group of ex-smokers included anyone having smoked in the past, occasionally or daily, and had abstained from smoking prior to the time of investigation. T he term "never smoker" designated people who had never smoked. T he quantities of tobacco smoked were calculated using the following equivalences: 1 cigar = 1 cigarillo = 2 cigarettes.
In addition to smoking status, the following data were extracted from the medical charts: age, sex, comorbidities, known to have potentially an impact on the prognosis of COVID-19, including diabetes, hypertension, obesity, immunodepression and respiratory disease S t a t i s t i c a l a n a l y s i s S t a t i s t i c a l a n a l y s i s   (P=0.045), immunodeficiencies in 3.0 % (P<0.0001), and COPD in 1.5% (P= 0.009). As shown in figure 1, age distribution differed between outpatients and inpatients, with outpatients being younger and inpatients being older.  T he daily cigarette consumption of current smokers is shown in T ABLE 3. In 2018, the mean number of daily cigarettes by current smokers in the French general population was 13.0 cigarettes, or equivalent, with 14.0 cigarettes for men and 11.9 for women [13].
T wo out of seven outpatients and 5/15 inpatients were heavy daily current smokers with a mean daily number of 20, or more cigarettes (data unavailable for 1 inpatient). outpatients and inpatients, suggesting that the protective effect of smoking covered the whole population of symptomatic (both non-severe and severe) patients.
One pending question was "Does smoking prevent SARS-CoV-2 from infecting a person, or does it affect the severity of the disease?" Our study is the first one to include and analyze separately the smoking pattern of COVID-19 outpatients (non-severe cases) and inpatients (severe cases). Indeed, all previous studies, but two, which reported smoking rates included only inpatients (T ABLE 1). Unfortunately, smoking data from inpatients and outpatients were mixed in the Guan study [1] and there was a lot of missing data in the report from the CDC [12]. It is of note that due to the low number of daily current smokers in our study, we could not conclude whether daily current smoking has an impact on COVID-19 severity. However, the SIR of inpatients did not differ from that reported in outpatients. In addition, the more severe COVID-19 patients, hospitalized in an ICU, were not included in the present study. A larger study including ICU patients will certainly help to conclusively address this question.
Because this is a cross-sectional study, we cannot confirm the causality of this association. We cannot also identify which of the many compounds of tobacco exerts the protective effect of smoking on COVID-19. T here are however, sufficient scientific data to suggest that smoking protection is likely to be mediated by nicotine. SARS-CoV2 is known to use the angiotensin converting enzyme 2 (ACE2) receptor for cell entry [14][15][16], and there is evidence that nicotine modulates ACE2 expression [17]which could in turn modulate the nicotinic acetyl choline receptor (manuscript submitted). We hypothesize that SARS-CoV2 might alter the control of the nicotine receptor by acetylcholine. T his hypothesis may also explain why previous studies have found an association between smoking and Covid-19 severity [1,9,10]. As hospitals generally impose smoking cessation and nicotine withdrawal at the time of hospitalization, tobacco (nicotine) cessation could lead to the release of nicotine receptors, that are increased in smokers, and to a "rebound effect" responsible for the worsening of disease observed in hospitalized smokers.
Our findings should be interpreted cautiously and we are aware of its limitations. First, the study was performed in 2020 and the results were compared to data obtained from the were estimated with the assumption that the studied population who lives in a limited area around a Parisian hospital has the same smoking habits as the general French population. Actually, smoking rates differ across socio-professional categories, and therefore may differ across geographic areas. It should also be noted that in the present study, healthcare workers were over-represented in the outpatient group, due to systematic testing at their work place when they become symptomatic, but not in the inpatient group (data not shown). It is, however, very unlikely that the very low SIRs that were estimated both for the out-and inpatient groups are the result of the study setting.
Under or over-reporting of smoking status may also be a concern for studies on smoking habits. It has been reported that smoking status tend to be more frequently reported in medical files of patients with comorbidities. However, our study has a very low rate of missing data regarding smoking status, and sensitivity analyses have shown that they do not alter the robustness of our results. Finally, in our study, smoking status was assessed only in symptomatic COVID-19 patients while a large part of infected individuals are asymptomatic [18] In conclusion, our results suggest that active smokers may be protected against symptomatic covid-19. T his was true for outpatients (who have less serious infections) as well as for hospitalized patients. Nicotine and the nicotinic receptor (and not the smoke of cigarettes per se, which is responsible for a very heavy public health burden with more than 78,000 deaths per year in France) may be indeed involved in the pathway leading to viral infection, and particularly in the most severe forms of the disease.
Nicotine administration, e.g. via a transcutaneous route may be tested as a therapy to recapitulate the protecting effect of smoking against SARS CoV2 infection.