Effects of Smoking on COVID-19 Management and Mortality: An Umbrella Review

Introduction Smoking status appears to lead to a poor prognosis in COVID-19 patients. However, findings from the studies conducted on this topic have not been consistent, and further exploration is required. Methods The objective of this umbrella review was to examine the effects of smoking on COVID-19 management and mortality. Online databases that included PubMed, Embase, Scopus, and Web of Science were searched using relevant keywords up to July 27, 2022. Articles were restricted to the English language, and the PRISMA protocol was followed. Results A total of 27 systematic reviews, published from 2020 to 2022, were included. Individual studies included in the systematic reviews ranged from 8 to 186, with various population sizes. The consensus from the majority of systematic reviews was that COVID-19 smoker patients experience greater disease severity, disease progression, hospitalization rate, hospital admission duration, mechanical ventilation, ICU admission, and mortality rate. Conclusions COVID-19 patients with a history of smoking (current and former) are vulnerable to adverse hospital outcomes and worse COVID-19 progression. Effective preventive and supportive approaches are required to decrease the risk of COVID-19 morbidity and mortality in patients with a history of smoking.

Smokers are more predisposed to viral and bacterial pulmonary infections including influenza, tuberculosis, and bacterial pneumonia [13][14][15][16]. In the first months of the pandemic in 2020, it was reported that Chinese patients with severe COVID-19 were mostly COPD patients or current smokers [17]. In addition, one of the earliest systematic reviews concluded that smoking is negatively associated with COVID-19 progression and prognosis [18]. Some studies have reported higher expression of angiotensin-converting enzyme 2 (ACE-2), which is the main receptor of SARS-CoV-2, in the lower respiratory airways of current smokers and COPD patients compared to nonsmokers, and stated that smoking and COPD could contribute to a higher COVID-19 incidence and relatively poorer outcomes [19,20]. Conversely, some studies have reported lower levels of ACE-2 among smokers compared to nonsmokers [21,22], and one preliminary meta-analysis of five studies in China stated smoking may not be significantly associated with an increased risk of severe disease among COVID-19 patients [23].
There have been five other meta-analyses conducted where the findings support the hypothesis that COPD and current smoking status contribute to worse progression and poor outcomes among COVID-19 patients [24][25][26][27][28]. One of the meta-analyses specifically stated that smoking can have negative adverse impacts on disease severity and mortality among hospitalized COVID-19 patients, with more impact on nondiabetic younger patients [27]. In addition, another meta-analysis specified that both current smoking and previous history of smoking increase COVID-19 severity significantly, while previous history of smoking increases the mortality risk [28]. Now that almost three years has passed since the first report of SARS-CoV-2 in human population, and large sample-sized studies and more reliable data are available, further investigation of COVID-19 and smoking is warranted. The aim of this review was to examine the associations between COVID-19 and smoking status (current smoker or history of smoking), answer the controversial paradoxes, and fill the gaps in the literature.

Methods
The objective of this umbrella study was to explore the prevailing systematic review literature pertaining the associations between COVID-19 and smoking status (being a current smoker or having history of smoking) and effects of smoking on COVID-19 management and mortality. In order to substantiate the results, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was followed. Quality of studies was evaluated with the NIH quality assessment tool.

Data
Sources. An extensive search of four online databases was performed which included PubMed, Scopus, Embase, and Web of Science as data sources. Articles were restricted to the English language, and the search was conducted up to July 27, 2022. The following keywords and their combinations were used during the search:

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2.2. Study Selection. In order to improve the study selection process, a two-step method was employed. The first step consisted of screening literature with regard to titles and abstracts. This was done by five researchers. The second step was performed by another five researchers, involving screening of full texts that were potentially eligible. Articles that met the inclusion criteria were advanced to the next step of data extraction. Articles were included if they had a systematic review nature and were peer-reviewed report on smoking and COVID-19. The exclusion criteria included studies lacking published data investigations, nonhuman research studies, duplications, abstracts with deficient full texts, editorial letters, conference abstracts, case series, and case reports.

Data Extraction.
Data of publications having met the eligibility criteria and passing the second step of selection process was meticulously extracted and gathered in Table 1. Five researchers investigated the full texts and extracted these study requisites. Any duplicates were removed, and the accuracy of the extracted data was checked.
2.4. Quality and Risk of Bias Assessment. Study quality and risk of bias was assessed with the National Institute of Health (NIH) Quality Assessment (QA) Tools for Case Series Studies. Two independent reviewers rated the quality of the included studies. Table 2 shows the results of the study quality and risk of bias. The scoring strategy of this tool has been explained at the bottom of this table.

Results
The database search yielded 113 potential studies (after duplicates removed), and following the screening, a total of 27 articles met the eligibility criteria ( Figure 1). The included systematic reviews were published between 2020 and 2022.
One study included was designed as reviews of reviews [33]. Included studies were from China, the USA, Spain, Greece, Thailand, Canada, Indonesia, Japan, and other countries. China (7 studies) and the USA (5 studies) were the countries most represented. The 27 systematic reviews included a wide range of studies (i.e., 8 to 186 studies) with different populations (from 17 to 1,304,587 patients among mentioned populations). Males were the dominant population in 6 studies [29,32,37,48,49]. Table 1 shows the characteristics of the studies.
Smoking history was categorized as smokers and nonsmokers in some studies [46,49], while most studies evaluated the smoking status as current and former smokers with comparisons between these groups [18,[40][41][42]47]. One study represented smokers based on smoking heaviness, lifetime smoking, and smoking initiation [39].
Most of the studies concluded that smoker's with COVID-19 had a worse outcome and higher mortality rate [27,30,34,36]. Evaluating the hospital admission rate, most of the studies showed increased risk of hospital admissions in smokers [18,29,30], while one study showed that smokers had lower risk of hospital admission [33].
The majority of studies found that smoking was associated with increased risk for mechanical ventilation [18,29,30]; however, there was one study showing no association between  [51]. These results are shown in Table 3.

Discussions
According to the NIH's LitCovid database, more than 291,000 articles related to COVID-19 have been published to date, which shows the explosion of research in this field. This incredible amount of research has increased the information on different aspects of the disease. However, knowledge is still lacking in some areas with further research required to better understand COVID-19 and its effects. This umbrella review is aimed at organizing and updating the existing body of literature on the effects of smoking on COVID-19.
The overall findings support the hypothesis of increased severity of disease in COVID-19 smoker patients. Specifically, smoking is linked to more advanced COVID-19 outcomes, as manifested by the necessity for ICU admission, mechanical ventilation, and COVID-19-related death. Nevertheless, only a few studies demonstrated no significant link between smoking and COVID-19-related mortality [30] and mechanical ventilation [51]. Additionally, only one study found no link between smoking and an increased risk of death from COVID-19 [27]. Notably, a study in England, that investigated approximately 17 million patient docu-ments, discovered that increased COVID-19-related mortality linked to smoking no longer remained significant after adjustment for the presence of preexisting chronic pulmonary disease. This suggests that smoking-induced comorbidities may be the cause of the overall death toll among COVID-19 smoker patients [53]. The results emphasize the need for further research elucidating the mechanisms by which smoking increases the incidence of unfavorable outcomes in COVID-19 patients.
Various potentially harmful compounds are present in tobacco products. Moreover, further chemicals are formed during aerosolization as a result of combustion or heating. Previous studies have demonstrated that pulmonary epithelium and vascular endothelium are both damaged by harmful compounds in cigarette smoke. The mucociliary clearance and epithelial barrier are compromised by damage to epithelial cells. Additionally, injured cells release modified molecules that activate specific lung receptors, activating acquired and innate immune responses [54]. Through a variety of mechanisms including the direct effect of nicotine, reperfusion injury after carbon monoxide-induced hypoxia, and particulate matter's abundance, tobacco smoke ingredients cause oxidative stress [55,56].
The angiotensin II conversion enzyme-2 (ACE2) receptor, which is abundant in mucosal respiratory epithelial cells,      [60]. Tobacco use can cause oxidative stress and inflammation in the lungs, making smokers more susceptible to bacterial or viral diseases [58,61]. Oxidative stress reduces epithelial permeability, which may have substantial consequences for smokers with COVID-19 disease [62,63]. Likewise, smoking leads to cardiovascular disease, chronic lung illness, diabetes, and other comorbidities that are related to worse outcomes in patients with COVID-19 infection [64]. On the contrary, there is evidence demonstrating that smoking may exert positive effects on COVID-19 disease severity, mediated by nicotine [51]. It is important to keep in mind that specific cigarette ingredients, like nicotine, may affect ACE2 differently from entire cigarettes [65]. The underlying mechanism might be attributed to the evidence showing nicotine might decrease tumor necrosis factor (TNF) expression in airway epithelial cells [66]. Moreover, nicotine may act as an agonist of the cholinergic anti-inflammatory pathway, which regulates the immune response and inflammatory reaction [67,68].
Factors responsible for higher susceptibility of smokers to COVID-19 are briefly discussed here to better understand the mechanisms about how smoking can affect the human body: (i) Smoking causes significant pathological changes including the mucosal epithelial barrier and an increase in the permeability of epithelial cells, which makes smokers more prone to be defeated against the virus invasion [69] (ii) Angiotensin-converting enzyme 2 (ACE 2) is defined as the principal receptor for SARS-CoV-2 virus to enter the host cell. ACE 2 expression is upregulated in the small airway epithelium of smokers, so the virus tends to invade host cells more easily. This upregulated receptor expression is one of the negative influences of oxidative stress due to smoking [20] (iii) Smoking can reduce the function of the immune system by causing a reduction in the number of CD4 + T cell (also named T helper cell, which activates macrophage or B cell), inhibiting the production of interleukin-22 (which moderates lung inflammation) and also, by promoting the secretion of catecholamines (which will weaken the immune system) [70,71] (iv) The most serious complication of COVID-19 disease is acute respiratory distress syndrome (ARDS), as a result of the cytokine storm. In this situation, large amounts of proinflammatory cytokines and chemokines such as IP-10, IL-6, TNF-α, IFN-γ, IL-2, IL-7, and GM-CSF are released and entail severe immune system response which eventually causes lung inflammation and damage. In former smokers, the expression of IL-6, TNF-α, and other proinflammatory factors are increased [72] Although most of the reviewed articles support the hypothesis that nicotine, the main component of cigarettes, increases the odds of developing severe illness of COVID-19, it is unknown whether the harm is related to nicotine or other toxic ingredients in cigarettes. Even some articles indicate that nicotine may have anti-inflammatory effects. Nicotine has been found to prevent acute lung damage and restrain the expression of tumor necrosis factor (TNF), which plays role in the inflammatory response [66]. Furthermore, nicotine is an agonist of the cholinergic anti-inflammatory pathway that modulates immune and inflammatory reaction [51,73].
There have been a few original research studies comparing former and current smokers. The lung may heal when someone quits smoking, which may bias the findings if former smokers are part of the exposed group since one study found that the death rate among former smokers reduces with age [44,45]. As a result, the frequency of smokers may have been underestimated, and some former smokers may have been incorrectly classified as nonsmokers [51]. As a result, only a few systematic reviews compared the features of these two groups. Three studies found that current smokers had lower risks of an adverse outcome than former smokers [31,35,51]. This might be because former smokers are more likely to be older, smoked for a longer period than current smokers, or because they have concomitant conditions such as asthma or COPD as a result of smoking [51]. Another factor might be that current smokers reported their status less than former smokers. [50], although a study found that current smokers had a greater likelihood of adverse outcomes than former smokers and nonsmokers [47].
Overall, compared with nonsmokers, smokers have higher risks of severe forms of the disease and hospitalization, and mortality [18,39,74]. On the contrary, the severity of COVID-19 was not associated with current or former smoking but with the comorbidities caused by smoking [75,76]. In this study, the incidence of infection by SARS CoV-2 virus in smokers and nonsmokers cannot be evaluated clearly due to the lack of data at this present time.

Conclusion
There is strong evidence that smoking increases the risks of disease severity/progression, hospitalization, and mortality among COVID-19 patients. Encouraging smokers to quit using, early initiation of treatment after the onset of symptoms, timely vaccination, and promoting other preventive behaviors by public health providers can control the possibility of these people getting the infection and a better prognosis. Vaccination of smokers should be done completely among the priority groups.

Data Availability
The authors stated that all information provided in this article could be shared.

Additional Points
Implications. (i) There is strong evidence that smoking increases the risks of disease severity/progression, hospitalization, and mortality among COVID-19 patients. (ii) Encouraging smokers to quit using, early initiation of treatment after the onset of symptoms, timely vaccination, and promoting other preventive behaviors by public health providers can control the possibility of these people getting the infection and a better prognosis. (iii) Vaccination of smokers should be done completely among the priority groups.

Disclosure
The present study was conducted in collaboration with the Khalkhal University of Medical Sciences, Iranian Institute for Reduction of High-Risk Behaviors, Tehran University of Medical Sciences, and the University of Sydney.

Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this manuscript.