Comparison of Clinical, Laboratory and Radiological Findings in Iranian Smokers and non- Smokers Patients with COVID-19: A Case Control Study

Objective: The current study compared the clinical, laboratory and radiological ndings between groups of smokers and non- smokers Iranian patients with COVID-19. Methods: This was a case-control study done on 120 patients with COVID-19 that were admitted to Baqiyatallah hospital, Tehran, Iran during March to May 2020. Our patients were categorized into two groups: smokers (40 patients) and non-smokers (80 age and sex matched controls). Demographic and clinical characteristics, laboratory ndings, imaging manifestations, and outcomes were compared between two age groups. Results: Regarding the comorbidities, no signicant difference was observed between the smoker and non-smoker patients. The distribution of COVID-19 symptoms was not signicantly different between smokers and non-smokers, except for chest pain and weakness, which were signicantly more common in smokers with COVID-19. A signicantly lower white blood cell count and neutrophils in peripheral blood sample of smokers however, no difference was found concerning lymphocyte count. Moreover, the RDW of smokers was signicantly lower. Regarding the ndings on CT scan of COVID-19 patients, no signicant difference was found between smoker and non-smoker COVID-19 patients. One (2.5%) of deaths occurred in the smoker and 3 (3.8%) occurred in the non- smoker groups. Conclusion: Current ndings showed that the clinical picture of smoker and non-smoker COVID-19 patients does not differ signicantly.


Introduction
The new corona virus (SARS-CoV-2) has caused the ongoing pandemic that has infected more than four million and killed more than 280,000 people until May 10th, 2020 (1). Patients typically experience mild u like symptoms, however a small proportion will progress to develop bilateral pneumonia and acute respiratory distress syndrome which may eventually result in death (2). Several studies have been conducted to identify the risk factors associated with severe disease and mortality. Comorbidities such as, cardiovascular diseases, COPD, diabetes, hypertension are thought to be associated with higher risk of severe disease (3,4).
A potential comorbidity for COVID-19 patients is smoking, and approximately 1.3 billion people smoke globally making smoking a widespread habit that can have signi cant impact on the prognosis of COVID-19 patients (5). Several studies have assessed the effect of smoking on the prognosis of COVID-19 however, the results of these studies are controversial (4,(6)(7)(8)(9)(10)(11)(12). Many studies suggest that smoking makes individuals more susceptible to COVID-19 and results in higher risk of severe disease and ICU admission (11,(13)(14)(15). Whereas, some studies implicate that not only smoking does not cause harm but also can have a protective role for patients with COVID-19, due to anti-in ammatory effects of nicotine (6,16,17). Therefore, the exact in uence of smoking on patients with COVID-19 still remains unknown.
In this study we sought to compare the symptoms, laboratory ndings and outcome of between smoker and non-smoker COVID-19 patients, and evaluate whether smoking changes the clinical course or outcome of COVID-19 patients.

Materials And Methods
This was a case-control study done on 120 patients with COVID- 19

Statistical analysis
Quantitative data are presented as mean ± standard deviation. Normality of distribution was evaluated using Kolmogorov-Smirnoff test. In order to assess the relationship between different variables, chisquare or sher extent tests were used for qualitative data and T-test and Mann-Whitney-U test were used for quantitative data, based on the distribution of data. Data analysis was done using SPSS version 23 and a p-value of less than 0.05 was considered statistically signi cant.

Results
Our study included 40 smoker COVID-19 patients and 80 age and sex matched non-smoker COVID-19 patients. The mean age of our patients was 51 ± 12 years and 74% of our patients were males. Mean BMI of our patients was 28.93 ± 6.08 kg/m 2 and no signi cant difference was noted between the two groups in case of BMI.
Regarding the comorbidities, no signi cant difference was observed between the smoker and non-smoker patients. The most common comorbidities in our study population were hypertension, diabetes and COPD (Table 1). As shown in Table 2, temperature, respiratory rate and oxygen saturation did not differ signi cantly between smokers and non-smokers. Moreover, as shown in Table 3, the distribution of COVID-19 symptoms was not signi cantly different between smokers and non-smokers, except for chest pain and weakness, which were signi cantly more common in smokers with COVID-19.  We also compared the laboratory ndings between smokers and non-smokers. Our results showed a signi cantly lower white blood cell count and neutrophils in peripheral blood sample of smokers however, no difference was found concerning lymphocyte count. Moreover, the RDW of smokers was signi cantly lower. Regarding other tests including CRP, ESR and creatinine no statistically signi cant difference was found between the two groups (Table 4). Regarding the ndings on CT scan of COVID-19 patients, no signi cant difference was found between smoker and non-smoker COVID-19 patients ( Table 5). The most common ndings of imaging was bilateral patchy ground glass opacities suggestive of viral or atypical pneumonia. Finally we compared the days of hospital stay and rate of discharge, readmission and death between smokers and non-smokers. As shown in Fig. 1 and Table 6, none of these aforementioned factors were statistically different among the two groups.

Discussion
Here we evaluated the clinical signs and symptoms, laboratory data, imaging ndings and outcomes of COVID-19 patients, and compared the smokers with non-smoker patients. Because it has been shown that age and gender signi cantly affect the clinical picture and outcome of COVID-19 patients (13, 18), we used an age and sex matched control group to eliminate the effect of age and sex in the comparison. Moreover, the prevalence of different comorbidities were not signi cantly different between smokers and non-smokers. Therefore, any differences in clinical picture or outcome of COVID-19 in our study, cannot be attributed to differences in comorbidities between smokers and non-smokers. Regarding the signs and symptoms of COVID-19, our data demonstrated that smokers are more likely to exhibit chest pain and weakness compared to non-smoker patients. In addition, the number of white blood cells and neutrophils were signi cantly lower in smokers. However, concerning the clinical outcome of COVID-19 patients, such as days of hospital stay, rate of discharge, readmission and death, our data indicated that no signi cant difference exists between smokers and non-smokers.
Since the start of SARS-CoV-2 epidemic, several studies have been carried out to identify the role of smoking in clinical picture and disease outcome, however the obtained results are contradictory. Apart from various editorials that have emphasized on the detrimental effects of smoking on COVID-19 patients and severity of the disease (19,20), many original articles and meta-analyses also indicated that smoker patients have a poorer prognosis compared to non-smokers (11,(13)(14)(15)21). Liu et al, evaluated 78 patients with COVID-19 and reported that patients with progressive disease were more likely to be smokers compared to patients who had improvement/stabilization (13). Moreover, they showed that patients with a history of smoking are roughly 14 times more likely to develop progressive disease. Two systematic reviews also demonstrated that smoking is a risk factor for more severe disease in COVID-19 patients (14,15). The main principle proposed for this increase in disease severity among smokers, is that smoking results in augmented expression of ACE-2 receptors in lung tissues, and as shown previously, SARS-CoV-2 exploits ACE-2 receptors to enter the pneumocytes and proliferate in them (20,21). Thus, smokers may be more susceptible to corona virus and experience more severe disease. Another plausible explanation is that smoking causes several diseases such as COPD and cardiovascular disease, which puts smokers at a higher risk compared to non-smokers (19). Accordingly, we excluded smoker patients with other comorbidities from our study and demonstrated that smokers do not differ from non-smokers in case of disease outcomes.
On the other hand, several authors suggested that smoking may not be as harmful as thought. through the α7 nicotinic acetyl choline receptors (α7-nAChRs). Ultimately, they suggested evaluating nicotine as an adjunct therapy for COVID-19 patients in clinical trials (6,17).
Our results are in line with two systematic reviews that showed smoking does not signi cantly affect the outcome of COVID-19 patients (18,22). This can be explained by the complex interplay of smoking and coronavirus. Although smoking may enhance the expression of ACE-2 receptors and expose patients to harmful chemical and make them susceptible to various diseases, its nicotine content may inhibit in ammatory responses thus neutralizing the detrimental effects of smoking for COVID-19 patients. Nevertheless we found some differences between smoker and non-smoker COVID-19 patients, including higher prevalence of weakness and chest pain and lower number of white blood cells and neutrophils in smokers. However, these differences are not clinically signi cant and does not change the clinical course or treatment options.
Our study had several limitations, for instance we did not evaluate other clinical outcomes such as the need for ICU admission or mechanical ventilation. Moreover, some patients' data were missing especially CT scan ndings of 45 patients were not available. However, having an age and sex matched control group with similar comorbidities compared to smoker COVID-19 patients is the strength of our study.

Conclusion
Our results showed that the clinical picture of smoker and non-smoker COVID-19 patients does not differ signi cantly, and in contrast to the common thought that smoking causes more severe disease in COVID-19 patients, our data showed no signi cant difference among smokers and non-smokers. Therefore we suggest that, even though smoking cannot be advertised as a treatment for COVID-19 due to its various detrimental effects, evaluating nicotine as an adjunct therapy may be a promising option. Declarations MN, AB and HA were responsible for study concept and design. AA, DGVO, AJ, MB, and AMG led data collection. HA, SRHZ, and AB were responsible for the analysis and interpretation of data. HA, AA and DGVO wrote the rst draft. AB, AA, DGVO, AJ, MB, and AMG contributed to the writing of the second and third draft. SRHZ provided comments on initial drafts and coordinated the nal draft. All authors read and approved the nal manuscript. All authors take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding
Thanks to nancial support, guidance and advice from the "Clinical Research Development Unit of Baqiyatallah Hospital".
Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Availability of data and materials
The data used in this study are available from the corresponding author on request.
Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki and Institutional Review Board approval has been obtained.

Consent for publication
By submitting this document, the authors declare their consent for the nal accepted version of the manuscript to be considered for publication.
23. Xu L, Chen G. Risk factors for severe corona virus disease 2019 (COVID-19) patients: a systematic review and meta analysis. medRxiv. 2020. Figure 1 Comparing the days of hospital stay between smokers and non-smokers with COVID-19