Document Type : Review article
Authors
1 College of Basic Education, University of Halabja, Halabja, Kurdistan Region, Iraq
2 Department of Chemistry, College of Sciences, University of Garmian, Kalar, Kurdistan Region, Iraq
3 Department of Medical Lab Technology, Kalar Technical College, Sulaimani Polytechnic University, Kalar, Kurdistan Region, Iraq
4 Immunology & Immuno-bioengineering Group, School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK
Abstract
Keywords
Main Subjects
Abstract
Background: Smoking is considered to be one of the main risk factors that may affect the severity of coronavirus disease 2019 (COVID-19). Previously, several meta-analyses with a limited or small sample size and insufficient methodology have been conducted investigating the impact of smoking on disease severity. Here, we use a more accurate method to identify the effect of smoking on COVID-19 disease severity.
Methods: BMC, PubMed, Science Direct, Wiley, Springer, and Google Scholar websites were used to search for and select reliable articles to be included in the current analysis. Research articles that mentioned the relationship between smoking and COVID-19 severity were included.
Results: Twenty-six research articles detailing 15,713 confirmed COVID-19 cases comprising patients who smoke were selected to be included in this analysis. The analysis showed a relationship between smoking, severe COVID-19, and non-severe COVID-19 (OR=0:11; 95%CI: 0.10–0.11; p<0.00001). Only 15% (2407) of the smokers suffered severe COVID-19, with the other 85% (13306) of smokers experiencing non-severe COVID-19.
Conclusion: The current analysis found that only 15% of severe COVID-19 cases were smokers. Therefore, smoking is not significantly correlated with severe covid19.
Keywords: COVID-19, Humans, Smokers, Smoking
Introduction
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has infected approximately 200 million people worldwide (1), causing a considerable public health threat and posing an immediate risk to the health of the global population (2). A number of factors have emerged that may cause an increased risk of severe outcomes and death from coronavirus disease 2019 (COVID-19) (3), including older age, male sex, smoking, race/ethnicity, nutrition, and having specific comorbid conditions such as hypertension, cardiovascular diseases, diabetes, liver diseases, pregnancy, and autoimmune disease (4-6).
There has been some argument regarding the impact of smoking on SARS-CoV-2 infection and subsequent COVID-19 severity, although it is well established that smokers face an increased risk of both viral and bacterial respiratory infections (7,8). Smoking tobacco causes cardiovascular disease and induces lung diseases, increasing the risk of respiratory infections, and the WHO has also highlighted smokers’ hand-to-mouth action as another factor that may cause smokers to be more susceptible to SARS-CoV-2 infection and development of COVID-19 (9,10). Available data concerning the effect of smoking on disease progression and death amongst COVID-19 patients is contradictory (11). Early in the pandemic, it was argued that higher mortality among males in China may reflect and be partly explained by the gender disparity in smoking prevalence (12). Smokers were not, however, identified as a vulnerable group within the UK Government’s COVID-19 guidance on social distancing (13).
A large study based on electronic health records from the United Kingdom identified a counterintuitive lower risk of COVID-19 mortality among smokers than among ex-smokers (14). A smaller French study also suggested that there were fewer smokers among COVID-19 patients than among the general French population (15). Conversely, other studies have linked the infection and severity of COVID-19 to smoking (16,17). In addition, smoking status, pack-years, and smoking intensity were correlated with hospitalizations in COVID-19 patients and smoking intensity was linked to ICU admission (18). Regarding these conflicting issues related to smoking and COVID-19, this study aims to determine the impact of smoking on COVID-19 severity, as well as the association between COVID-19 outcome and age in smokers that pave a way for COVID-19 treatment guidelines and further research in this area.
Materials and Methods
Ethical approval and informed consent were not required for this study because it was conducted using published studies.
Search
We used search machines on the BMC, PubMed, ScienceDirect, Wiley, Springer, and Google Scholar websites to select a number of appropriate papers to be included in the current analysis. To find studies for the analysis, papers published between January 1, 2020 and July 1, 2021 were searched using the key-words/phrases ‘coronavirus and smoking’, ‘smoking and COVID-19 severity’, ‘COVID-19 and health conditions’, ‘smoking and risk of COVID-19’, and ‘relationship between smoking and COVID-19’.
Paper inclusion and exclusion
Papers that met the following conditions were included in the analysis: 1) described the relationship between COVID-19 and smoking; 2) were written in English; 3) were published between January 1, 2020 and July 1, 2021; 4) mentioned the severity of COVID-19 due to smoking. Papers were excluded from this study if they: 1) were not written in English; 2) did not clearly explain the relationship between severities of COVID-19 and smoking; and/or 3) were case reports or editorial letters.
Data extraction
Article titles and abstracts were scanned to find appropriate studies to be included in the next step, in which the full text of the selected the articles were evaluated to determine if they would be included in or excluded from the study. The following features were extracted from all the papers: title, authors, publication date, location, age, sample size, and if COVID-19 was described as severe (critical, severe, ICU, non-survivors) or non-severe (mild, common type, non-ICU, survivors). Patient numbers from a study by Bhaskaran et al (19) were adjusted (divided by 1000) to be closer to the range of the other papers.
Ethics declarations
All methods were used in accordance with relevant guidelines and regulations. The current study analysed other studies without involving any COVID-19 patient.
Statistical analysis
Revman version 5.4 was used to calculate odds ratios with 95% confidence intervals, which were depicted using a forest plot. For evaluating heterogeneity between studies, chi-square and I-square were used. Python 3.8.8 was used for data management and study plots.
Results
The initial search identified 489 articles, but after removing the duplicates, 309 articles remained. Based on the abovementioned exclusion criteria, 283 of these articles were excluded from the study, resulting in 26 articles remaining to be included in the quantitative analysis (Figure 1). These articles included 15,713 hospitalised COVID-19 patients; 2,704 severe cases and 13,306 non-severe cases (Figure 2).
Three studies (20-22) were conducted on COVID-19 populations of fewer than 10 patients; 14 studies involved population studies of 10–100 patients (23-36); four studies (37-40) consisted of 100–1000 COVID-19 patients; and five studies (19,41-44) included thousands of patients.
The current study included 10 studies (20-24,26,31, 32,37,38) from China, which consisted of 619 patients; 119 severe cases and 427 non-severe. Five studies included here occurred in the US (30,39,41,43,44) comprising 4,168 COVID-19 patients; 1,564 severe and 2,604 non-severe. The UK offered the largest sample size, 8,716 patients (11 severe and 8,705 non-severe) (19). A single study was included from each of the following countries: Spain (1,221 samples; 336 severe and 885 non-severe) (42); Italy (567 samples; 167 severe and 391 non-severe) (40); Qatar (98 samples; 30 severe and 68 non-severe) (36); Pakistan (72 samples; 13 severe and 59 non-severe) (35); Iraq (71 samples; 28 severe and 43 non-severe) (34); Turkey (68 samples; eight severe and 60 non-severe) (33); Brazil (38 samples; 18 severe and 16 non-severe) (29); Israel (33 samples; 10 severe and 23 non-severe) (28); Japan (29 samples; 12 severe and 17 non-severe) (27); and Egypt (17 samples; nine severe and eight non-severe) (25) (Table 1).
Table 1. The Table shows the summary and features of the selected papers to include in the analysis. Bhaskaran et al 18 cases have been divided by 1000
|
Author |
Study |
Publication date |
Location |
Age |
Sample size (N) |
Severe |
non-severe |
|
Prinelli et al |
Association between smoking and SARS-CoV-2 infection: cross-sectional study of the EPICOVID19 internet-based survey 39 |
April/2021 |
Italy |
48 |
567 |
176 |
391 |
|
Guan et al |
Clinical characteristics of coronavirus disease 2019 in China 36 |
Feb/2020 |
China |
40 |
158 |
38 |
120 |
|
Abbas et al |
Presenting the characteristics, smoking versus diabetes, and outcome among patients hospitalized with COVID-19, 33 |
Jan/2021 |
Iraq |
48 |
71 |
28 |
43 |
|
Nassar et al |
Outcomes and risk factors for death in patients with coronavirus disease-2019 (COVID-19) pneumonia admitted to the intensive care units of an Egyptian University Hospital: A retrospective cohort study 24 |
June/2021 |
Egypt |
60 |
17 |
9 |
8 |
|
Merzon et al |
Haemoglobin A1c is a predictor of COVID-19 severity in patients with diabetes 27 |
Sept/2020 |
Israel |
59 |
33 |
10 |
23 |
|
Gupta et al |
SARS-CoV-2 infection and smoking: what is the association? A brief review 37 |
March/2021 |
China |
65 |
277 |
97 |
180 |
|
Shelton et al |
Trans-ancestry analysis reveals genetic and non-genetic associations with COVID-19 susceptibility and severity 40 |
April/2021 |
USA |
51 |
1207 |
74 |
1133 |
|
Afridi et al |
Elemental concentrations in biological samples of coronavirus disease (COVID-19) and other pulmonary disease patients 34 |
May/2021 |
Pakistan |
32 |
72 |
13 |
59 |
|
Marouf et al |
Association between periodontitis and severity of COVID-19 infection- A case–control study 35 |
April/2021 |
Qatar |
29 |
98 |
30 |
68 |
|
Li et al |
Tobacco smoking confers risk for severe COVID-19 unexplainable by pulmonary imaging 30 |
March/2021 |
China |
58 |
56 |
22 |
34 |
|
Bauer et al |
Hypertension medications and risk of severe COVID-19 -A Massachusetts community-based observational study 38 |
Jan/2021 |
USA |
61 |
331 |
88 |
243 |
|
Hu et al |
Predictive value of the prognostic nutritional index for the severity of coronavirus disease 2019 20 |
Dec/2020 |
China |
44 |
8 |
3 |
5 |
|
Zhong et al |
Which factors, smoking, drinking alcohol, betel quid chewing, or underlying diseases, are more likely to influence the severity of COVID-19? 25 |
Jan/2021 |
China |
64 |
17 |
2 |
15 |
|
Espejo-Paeres et al |
Impact of smoking on COVID-19 outcomes: a HOPE registry sub analysis 41 |
June/2021 |
Spain |
66 |
1221 |
336 |
885 |
|
Puebla Neira et al |
Smoking and risk of COVID-19 hospitalization 43 |
April/2021 |
USA |
42 |
1315 |
273 |
1042 |
|
Ho et al |
Controversy over smoking in COVID-19—A real world experience in New York city 42 |
Dec/2020 |
USA |
58 |
1279 |
1117 |
162 |
|
Araújo et al |
Health conditions of potential risk for severe COVID-19 in institutionalized elderly people 28 |
Jan/2021 |
Brazil |
70 |
34 |
18 |
16 |
|
Kara et al |
Grip strength as a predictor of disease severity in hospitalized COVID-19 patients 32 |
June/2021 |
Turkey |
55 |
68 |
8 |
60 |
|
Bhaskaran et al |
Factors associated with deaths due to COVID-19 versus other causes- population-based cohort analysis of UK primary care data and linked national death registrations within the Open SAFELY platform 18 |
May/2021 |
UK |
49 |
8716 |
11 |
8705 |
|
Peng et al |
Smoking is correlated with the prognosis of coronavirus disease 2019 (COVID-19) patients an observational study 31 |
March/2021 |
China |
55 |
62 |
14 |
48 |
|
Zhou et al |
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China a retrospective cohort study 22 |
March/2020 |
China |
61 |
11 |
5 |
6 |
|
Wang et al |
Epidemiological and clinical features of 125 Hospitalized Patients with COVID-19 in Fuyang Anhui China 23 |
April/2020 |
China |
50 |
16 |
7 |
9 |
|
Brawner et al |
Inverse relationship of maximal exercise capacity to hospitalization secondary to coronavirus disease 2019, 29 |
Oct/2020 |
USA |
65 |
36 |
12 |
24 |
|
Yao et al |
Experience of 101 patients with coronavirus infectious disease 2019 (COVID-19) at a tertiary care center in Japan 26 |
Dec/2020 |
Japan |
60 |
29 |
12 |
17 |
|
Liu et al |
Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease 19 |
May/2020 |
China |
38 |
5 |
3 |
2 |
|
Wan et al |
Clinical features and treatment of COVID?19 patients in northeast Chongqing 21 |
April/2020 |
China |
46 |
9 |
1 |
8 |
The ages of patients ranged from 29 years 35 to 70 years (29). Eight studies (23,25-27,30,38,39,42) involved patients between 60 and 69 years of age; seven studies (24,28,31-33,41,43) included patients between 50 and 59 years of age; and another seven articles (19,21,22,34,37,40,44) had patients between 40 and 49 years of age. The mean age of samples in two studies were 38 (20) and 32 years (34) (Figure 3).
In our multi-analysis study, we found that 15% of the COVID-19 patients with smoking habits had experienced severe symptoms, whereas the rest experienced non-severe symptoms (Figure 4).
Discussion
In this review, data from the BMC, PubMed, ScienceDirect, Wiley, Springer, and Google Scholar websites were analysed to show the impact of smoking on COVID-19 severity. This review evaluated literature concerning the link between smoking and COVID-19, including the likelihood of SARS-CoV-2 infection and COVID-19 hospitalisation, and the severity of COVID-19 outcomes among hospitalised patients, such as admission to critical care units.
The 26 studies analysed are presented in table 1. Overall, 8,723,756 COVID-19 patients with smoking habits from around the world were selected for inclusion in this analysis. A total of 16,280 of these patients were hospitalised. The results of our meta-analysis represented that smoking patients might face a lower risk of developing severe or mortal COVID-19, as 85% (13,306 patients) experienced non-severe COVID-19, with only 15% (2,407 patients) suffering increased severity of disease (OR =0:11; 95%CI: 0.10–0.11; p<0.00001).
Generally, fever, cough, and sputum are the most prevalent clinical symptoms in COVID-19 patients. Normal body temperature may be a sign of a poor immune response in a patient. Shortness of breath, often known as dyspnoea, indicates a shortage of oxygen and poor lung function. As a result, if the patient has trouble breathing but no temperature, it is important to remain on the lookout for future deterioration of the patient’s condition (45).
Even though, limitations add to misclassification errors in number of studies, which can lead to biased results toward the null and underestimates the risk of smoking in increasing COVID-19 severity (46).
The findings of our meta-analysis may be useful in determining the impact of smoking status on illness progression, complications, and death in COVID-19 patients who are hospitalised. Two recent studies used univariate analysis to find a link between smoking and poor outcomes in COVID-19 patients who were hospitalised, although the links were not always statistically significant (16,17).
SARS-CoV-2 attaches to the receptor for Angioten-sin-Converting Enzyme 2 (ACE2), which has generally protective effects on the lungs, and then downregulates it; hence, any condition that causes ACE2 levels to drop may supply the virus with fewer binding sites. It has been reported that smoking can upregulate ACE2 (47), but it is also known from animal models that chronic cigarette exposure can reduce ACE2 expression in lung tissues (48). More data show that nicotine alters the renin-angiotensin system’s function by upregulating the ACE-mediated axis while downregulating the compensatory ACE2-mediated axis (49). Moreover, a nicotine-induced increase of ACE activity could lead to an increased degradation of bradykinin, one of the most potent inflammatory mediators in humans, which is able to activate signalling pathways resulting in increased vascular permeability, oedema, vasodilation, hy-potension, pain, and fever, all typical features of COVID-19 (50).
Our findings indicate that smoking increases the progression of COVID-19 severity, in line with previous meta-analysis studies that have clearly demonstrated a significant relationship between smoking and patients with severe COVID-19 (51-54). Although no clear conclusions can be drawn regarding the particular effects of smoking on the risk of COVID-19 hospitalisation, tobacco cigarette smoke contains numerous toxins and other substances that are not known to have any immunomodulatory or antiviral characteristics that might protect against COVID-19. Nicotine, however, is a major component of tobacco cigarette smoke, and was reported to protect acute lung damage and decrease TNF expression in airway epithelial cells in vitro in an animal Acute Respiratory Distress Syndrome (ARDS) model (55). Nicotine is a cholinergic anti-inflammatory agonist that controls the immunological and inflammatory responses of the host, and has also been shown to have anti-inflammatory effects in individuals who have been exposed to endotoxins in vivo (55). Nicotine suppresses the production of pro-inflammatory cytokines like TNF, IL-1, and IL-6 while not suppressing the production of anti-inflammatory cytokines like IL-10 (57). In addition, smoking increases the severity and mortality of both bacterial and viral infections through the induction of mechanical and structural changes in the respiratory tract and alteration of cell‐ and humoral‐mediated immune responses (58,59).
In contrast, antibodies against cytokine-mediated illnesses such as sepsis and endotoxemia, which cause organ damage and death, have been discovered. The condition known as ‘cytokine storm’ is characterised by an enhanced production of pro-inflammatory cytokines in response to infections, which can develop to ARDS. This phenomenon appears to have a role in the pathophysiology of severe COVID-19 and might explain the histological findings in a COVID-19 patient after death (60,61). Medicines that target pro-inflammatory cytokines, such as IL-1 or IL-6 inhibitors, have therefore been proposed for and are now being investigated in clinical studies to treat COVID-19 patients by neutralising these important inflammatory mediators (62). The US FDA recently approved a Phase III clinical trial of an IL-6 inhibitor for the treatment of COVID-19 (63). As a result, the cytokine storm has been identified as a therapeutic target in COVID-19 patient clinical trials, and nicotine’s effects on the immune system may be useful in decreasing the severity of the cytokine storm.
Conclusion
To conclude, our analysis demonstrated that smoking was not contributed to increased severity of COVID-19, as 15% of COVID-19 cases among smokers were severe. This is a higher percentage than that among the whole COVID-19 patient population, most likely due to the effect of smoking on COVID-19 disease pathology, which requires further studies.
Conflict of Interest
Not applicable.
References
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