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      Systematic review of the prevalence of current smoking among hospitalized COVID‑19 patients in China: could nicotine be a therapeutic option?

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      Internal and Emergency Medicine
      Springer International Publishing

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          Abstract

          Dear Editor, We read with great interest the article by Farsalinos et al. [1] recently published in Internal and Emergency Medicine. The review [1] of 13 studies enrolling a total of 5960 hospitalized coronavirus disease 2019 (COVID-19) patients in China revealed unusually lower (approximately one-fourth) smoking prevalence in COVID-19 cases than that in the general population. Recent meta-analyses [2, 3], however, demonstrated that smoking was associated with worse prognosis and mortality in patients with COVID-19. To determine whether COVID-19 prevalence is modulated by smoking prevalence, meta-regression of Japanese prefectural data was herein conducted. In each Japanese prefecture, the following was extracted: (1) number of confirmed COVID-19 cases on 15 June 2020 from the “Ministry of Health, Labour and Welfare” (https://www.mhlw.go.jp/content/10906000/000640393.pdf); (2) smoking prevalence (%) in 2016 (latest survey) from the “National Cancer Center Japan” (https://ganjoho.jp/reg_stat/statistics/dl/index.html#smoking); and (3-1) population per 1-km2 inhabitable area (in 2018), (3-2) proportion (%) of males and < 15-year/≥ 65-year subjects (in 2018), (3-3) prevalence (/100 thousands) of neoplasm, type 2 diabetes mellitus, and essential hypertension (in 2017), (3-4) yearly average air temperature (°C), total sunshine hours (h), total precipitation (mm), and average relative humidity (%) (in 2018), (3-5) healthy life expectancy (years) (in 2016) and life expectancy at birth (years) (in 2015), (3-6) number (/100 thousands) of hospital beds (in 2017), doctors (in 2017), and nurses (in 2018), (3-7) monthly average households and persons assisted by livelihood protection (/1000 persons) (in 2017), and (3-8) monthly current income per household and living expenditure (≥ 2-person households–workers’ households) (yen) (in 2018) from the “e-Stat, Statistics of Japan” (https://www.e-stat.go.jp) (Supplementary Table S1). To adjust for prefectural population density, COVID-19 prevalence was defined as the number of COVID-19 cases divided by the population per 100-km2 inhabitable area. Univariable (including smoking prevalence as only a covariate) and multivariable (including all the above-mentioned parameters as covariates) random-effects meta-regression was performed using OpenMetaAnalyst (https://www.cebm.brown.edu/openmeta/index.html). A meta-regression graph depicted COVID-19 prevalence (plotted as logarithm-transformed prevalence on the Y-axis) as a function of smoking prevalence (plotted on the X-axis). A slope of the univariable meta-regression line was significantly positive (coefficient, 0.319; 95% confidence interval [CI] 0.148–0.490; p < 0.001; Fig. 1), which indicated that COVID-19 prevalence increased significantly as smoking prevalence increased. The slope was also significantly positive (coefficient, 0.321; 95% CI 0.093–0.549; p = 0.006) even in multivariable meta-regression including all the 22 covariates together (Table 1). Fig. 1 Meta-regression graph depicting COVID-19 prevalence (plotted as logarithm-transformed prevalence on the Y-axis) as a function of smoking prevalence (plotted on the X-axis) Table 1 Multivariable meta-regression summary Covariate Coefficient 95% confidence interval p value Lower Upper Smoking (%) 0.321 0.093 0.549 0.006 Male (%) – 0.323 – 0.892 0.247 0.267 < 15 years (%) – 0.452 – 1.326 0.423 0.311 ≥ 65 years (%) – 0.313 – 0.659 0.034 0.077 Neoplasm (/100 thousands) – 0.000 – 0.000 0.000 0.577 Type 2 diabetes mellitus (/100 thousands) 0.007 – 0.002 0.015 0.116 Essential hypertension (/100 thousands) – 0.009 – 0.021 0.003 0.136 Yearly average air temperature (°C) 0.146 – 0.166 0.457 0.359 Yearly total sunshine hours (h) – 0.001 – 0.003 0.001 0.178 Yearly total precipitation (mm) 0.000 – 0.001 0.001 0.905 Yearly average relative humidity (%) – 0.036 – 0.116 0.043 0.371 Healthy life expectancy, male (years) 0.077 – 0.537 0.692 0.805 Healthy life expectancy, female (years) 0.247 – 0.170 0.664 0.246 Life expectancy at birth, male (years) 0.652 – 0.567 1.870 0.294 Life expectancy at birth, female (years) – 0.404 – 1.911 1.102 0.599 Hospital beds (/100 thousands) – 0.001 – 0.003 0.002 0.708 Doctors (/100 thousands) – 0.010 – 0.024 0.003 0.127 Nurses (/100 thousands) 0.003 – 0.003 0.010 0.354 Monthly average households assisted by livelihood protection (/1000 households) – 0.206 – 0.440 0.028 0.085 Monthly average persons assisted by livelihood protection (/1000 persons) 0.379 – 0.003 0.762 0.294 Monthly current income per household (yen) 0.000 – 0.000 0.000 0.883 Monthly living expenditure (yen) 0.000 – 0.000 0.000 0.520 The present meta-regression suggests a positive association of smoking prevalence with COVID-19 prevalence independent of various examined covariates. Remarkably lower current-smoking prevalence in hospitalized COVID-19 patients (6.5%; 95% CI 4.9–8.2%) than that in the general population (26.6%) in China (2018 Global Adult Tobacco Survey, https://www.who.int/docs/default-source/wpro---documents/countries/china/2018-gats-china-factsheet-cn-en.pdf?sfvrsn=3f4e2da9_2) has been reported in the article by Farsalinos et al. [1], which could be explained by nicotine-induced downregulation of the angiotensin converting enzyme 2 (ACE2) receptor [4], i.e. the receptor for severe acute respiratory syndrome coronavirus 2 causing COVID-19. This hypothesis, however, may be negated by the present findings of the positive association of smoking prevalence with COVID-19 prevalence in Japan. The interplay between smoking and COVID-19 may be exceedingly complicated and should not be oversimplified by the ACE2 hypothesis. Despite well documenting the smoking risk on health, tobacco/cigarette smoke (e.g. nicotine, carbon monoxide, and menthol) is experimentally known to positively modulate the immune system and may exert both harmful and beneficial influences [5]. The main limitations of the present analysis included relatively small number of COVID-19 cases in each prefecture and latest survey of smoking prevalence 4 years before the study period investigating COVID-19 prevalence in 2020. It should be noted that the present results do not denote directly that smokers are at high risk for COVID-19. The present findings demonstrate simply that the COVID-19 prevalence is higher in the prefecture where smoking prevalence is higher. However, the present results could be strengthened and explained by the reported association of smoking with worse prognosis and mortality in COVID-19 patients [1, 2]. In conclusion, smoking may be independently associated with COVID-19, which should be confirmed by further experimental, clinical and epidemiological investigations. Electronic supplementary material Below is the link to the electronic supplementary material. Supplementary file1 (PDF 114 kb)

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          Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis

          Background An epidemic of Coronavirus Disease 2019 (COVID-19) began in December 2019 and triggered a Public Health Emergency of International Concern (PHEIC). We aimed to find risk factors for the progression of COVID-19 to help reducing the risk of critical illness and death for clinical help. Methods The data of COVID-19 patients until March 20, 2020 were retrieved from four databases. We statistically analyzed the risk factors of critical/mortal and non-critical COVID-19 patients with meta-analysis. Results Thirteen studies were included in Meta-analysis, including a total number of 3027 patients with SARS-CoV-2 infection. Male, older than 65, and smoking were risk factors for disease progression in patients with COVID-19 (male: OR = 1.76, 95% CI (1.41, 2.18), P 40U/L, creatinine(Cr) ≥ 133mol/L, hypersensitive cardiac troponin I(hs-cTnI) > 28pg/mL, procalcitonin(PCT) > 0.5ng/mL, lactatede hydrogenase(LDH) > 245U/L, and D-dimer > 0.5mg/L predicted the deterioration of disease while white blood cells(WBC) 40U/L:OR=4.00, 95% CI (2.46, 6.52), P 28 pg/mL: OR = 43.24, 95% CI (9.92, 188.49), P 0.5 ng/mL: OR = 43.24, 95% CI (9.92, 188.49), P 245U/L: OR = 43.24, 95% CI (9.92, 188.49), P 0.5mg/L: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001; WBC < 4 × 109/L: OR = 0.30, 95% CI (0.17, 0.51), P < 0.00001]. Conclusion Male, aged over 65, smoking patients might face a greater risk of developing into the critical or mortal condition and the comorbidities such as hypertension, diabetes, cardiovascular disease, and respiratory diseases could also greatly affect the prognosis of the COVID-19. Clinical manifestation such as fever, shortness of breath or dyspnea and laboratory examination such as WBC, AST, Cr, PCT, LDH, hs-cTnI and D-dimer could imply the progression of COVID-19.
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            The impact of COPD and smoking history on the severity of COVID‐19: A systemic review and meta‐analysis

            Abstract Comorbidities are associated with the severity of coronavirus disease 2019 (COVID‐19). This meta‐analysis aimed to explore the risk of severe COVID‐19 in patients with pre‐existing chronic obstructive pulmonary disease (COPD) and ongoing smoking history. A comprehensive systematic literature search was carried out to find studies published from December 2019 to 22 March 2020 from five databases. The languages of literature included English and Chinese. The point prevalence of severe COVID‐19 in patients with pre‐existing COPD and those with ongoing smoking was evaluated with this meta‐analysis. Overall 11 case series, published either in Chinese or English language with a total of 2002 cases, were included in this study. The pooled OR of COPD and the development of severe COVID‐19 was 4.38 (fixed‐effects model; 95% CI: 2.34‐8.20), while the OR of ongoing smoking was 1.98 (fixed‐effects model; 95% CI: 1.29‐3.05). There was no publication bias as examined by the funnel plot and Egger's test (P = not significant). The heterogeneity of included studies was moderate for both COPD and ongoing smoking history on the severity of COVID‐19. COPD and ongoing smoking history attribute to the worse progression and outcome of COVID‐19.
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              Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option?

              The effects of smoking on Corona Virus Disease 2019 (COVID-19) are currently unknown. The purpose of this study was to systematically examine the prevalence of current smoking among hospitalized patients with COVID-19 in China, considering the high-population smoking prevalence in China (26.6%). A systematic review of the literature (PubMed) was performed on April 1. Thirteen studies examining the clinical characteristics of hospitalized COVID-19 patients in China and presenting data on the smoking status were found. The pooled prevalence of current smoking from all studies was calculated by random-effect meta-analysis. To address the possibility that some smokers had quit shortly before hospitalization and were classified as former smokers on admission to the hospital, we performed a secondary analysis in which all former smokers were classified as current smokers. A total of 5960 patients were included in the studies identified. The current smoking prevalence ranged from 1.4% (95% CI 0.0–3.4%) to 12.6% (95% CI 10.6–14.6%). An unusually low prevalence of current smoking was observed from the pooled analysis (6.5%, 95% CI 4.9–8.2%) as compared to population smoking prevalence in China. The secondary analysis, classifying former smokers as current smokers, found a pooled estimate of 7.3% (95% CI 5.7–8.9%). In conclusion, an unexpectedly low prevalence of current smoking was observed among patients with COVID-19 in China, which was approximately 1/4th the population smoking prevalence. Although the generalized advice to quit smoking as a measure to reduce health risk remains valid, the findings, together with the well-established immunomodulatory effects of nicotine, suggest that pharmaceutical nicotine should be considered as a potential treatment option in COVID-19.
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                Author and article information

                Contributors
                kfgth973@ybb.ne.jp
                Journal
                Intern Emerg Med
                Intern Emerg Med
                Internal and Emergency Medicine
                Springer International Publishing (Cham )
                1828-0447
                1970-9366
                16 August 2020
                : 1-3
                Affiliations
                GRID grid.415810.9, ISNI 0000 0004 0466 9158, Shizuoka Medical Center, ; 762-1 Nagasawa, Shimizu-cho, Sunto-gun, Shizuoka, 411-8611 Japan
                Author information
                http://orcid.org/0000-0002-5594-8072
                Article
                2473
                10.1007/s11739-020-02473-2
                7429138
                6c802f3b-7dbe-4b5b-9ff6-167c558d6adb
                © Società Italiana di Medicina Interna (SIMI) 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 6 July 2020
                : 6 August 2020
                Categories
                Ce - Letter to the Editor

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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