Association of Smoking Status with Outcomes in Hospitalized COVID-19 Patients

Introduction: Smoking causes in�ammation of the lung epithelium by releasing cytokines and impairing muco-ciliary clearance. Some studies have linked smoking with severity of illness of COVID-19 whereas others have found no such association. Methods: This was a retrospective analysis of all adults hospitalized with COVID-19 from March 09 to May 18, 2020. Results: 1173 patients met the study criteria. 837 patients never smoked and 336 patients were either current smokers or past smoker and were grouped together in smokers group. Patients in smokers group were more likely to be male and had higher incidence of underlying COPD (19% vs. 6%, p<0.001), human immunode�ciency virus infection (11% vs. 5%,p<0.001), cancer (11% vs. 6%, p=0.005), congestive heart failure (15% vs. 8%, p<0.001), coronary artery disease (15% vs. 9%, p=0.027), chronic kidney disease (11% vs. 8%, p=0.037), and end-stage renal disease (10% vs. 6%, p=0.009) compared to non-smokers. Smokers were more likely to develop critical illness requiring mechanical ventilation (47% vs. 37% p=0.005). Univariate Cox model for survival analysis by smoking status showed that smokers only current smokers had higher risk of death compared to never-smokers (HR 1.61, 95% con�dence interval 1.22–2.12, p<0.001). In the multivariate approach Cox model for the survival, female sex, age, LDH and systemic steroid use were associated with overall survival. Conclusion: In our large single center retrospective database of patients hospitalized with COVID-19, smoking was associated with development of critical illness and higher likelihood of death


Introduction
The coronavirus pandemic began in December 2019 and has rapidly spread globally. 1The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), which belongs to the subgenu Sarbecovirus (Beta-CoV lineage B), Orthocoronavirinae subfamily. 2SARS-COV-2 predominantly affects the respiratory tract by entering the alveolar epithelial cells via ACE2 receptors.The virus also uses activation of spike proteins to enter the cells. 3Symptoms vary signi cantly from an asymptomatic infection to severe acute respiratory distress syndrome (ARDS).
Smoking has been considered a risk factor for many respiratory viral illnesses including in uenza, MERS, RSV, etc. 4,5 Smoking leads to in ammation of the lung epithelium causing release of cytokines, increased mucous secretion, impaired mucociliary clearance as well as epithelial cell damage.In a descriptive study, Guan et al 1 showed that current and former smokers were more likely to present with severe coronavirus disease 2019 (COVID-19).In another small study, Liu et al showed that smoking history was associated with progression of COVID-19. 5Contrary to these ndings, study by Huang et al, showed that current smoking history is not associated with need for ICU care. 6Similar ndings were observed by subsequent larger observational studies. 7,8 otine is known to have a role in immunomodulation and regulation of ACE 2 receptors.In a recent study, ever-smokers were shown to have higher pulmonary ACE2 receptor expression by 25% compared to never-smokers.These ndings suggested that ever smokers have increased risk of viral binding and entry into the lungs. 9Current literature evaluating difference in outcomes between current smokers, past smokers and never smokers is sparse.Our hospital is located in New York City where 13.1% of the residents' smoke. 10Bronx was also one of the hardest hit boroughs of the New York City during the COVID-19 pandemic. 11In this retrospective study, we aimed to analyze the effects of smoking habits in the outcomes of patients hospitalized with COVID-19 illness.

Study Setting
We conducted this study at BronxCare Health System (BCHS), the largest voluntary, not-for-pro t health and teaching hospital system, serving the south and central Bronx in the New York City.We retrospectively analyzed all consecutively hospitalized adults with COVID-19 from March 09 to May 18, 2020.A diagnosis of COVID-19 was established when a patient tested positive for the virus SARS-CoV-2 from the polymerase chain reaction (PCR) analysis of nasopharyngeal swab specimens at any point during their hospitalization.This study was approved by the institutional review board at BCHS under an expedited review in the setting of a global pandemic (IRB # 06 11 20 09).Need for consent was waived due to retrospective nature of the study.

Participants and eligibility criteria
We included adult patients with known smoking status who were hospitalized with COVID-19 for whom severity of illness could be established and had nal disposition status at the time of the study.1336 adult patients were admitted with COVID-19 during the study period.Smoking status was not known for 112 patients.Another 34 patients were still admitted at the time of data analysis and were excluded because their nal outcome was not known for survival to hospital discharge analysis.17 patients were excluded because the disease severity could not be established due to missing data elements (Fig. 1).1173 (87.8%) patients met the study inclusion criteria.
During the study period, an inpatient guide for the management of COVID-19 was developed by the Department of Medicine, and distributed to all healthcare providers at our hospital.Patients admitted during the study period received supportive and therapeutic modalities based on individual physician's clinical discretion and our inpatient guide.
We extracted our data manually from electronic medical records.The data obtained included patients' demographic details, comorbidities, self-reported smoking history, laboratory and radiological test results, medication administration history, and ventilator requirement data.
Study outcomes were de ned as severity of illness and mortality.

Severity of illness
Hypoxia was de ned as oxygen saturation of ≤ 94% Mild illness was de ned as upper respiratory illness without any evidence of pneumonia or hypoxia Moderate illness was de ned as radiographic evidence of pneumonia without hypoxia Severe illness was de ned as radiographic evidence of pneumonia with hypoxia requiring any form of supplemental oxygen or non-invasive positive pressure ventilation Critical illness was de ned as need for invasive mechanical ventilation

Statistical Analysis
We used univariate analysis chi-square test for comparing categorical variables between smokers and non-smokers.Because the normality assumption was violated for continuous variables, the nonparametric Mood's median test was used to compare the two groups.To compare the survival times log-rank test was used.Additionally, the Kaplan Meier estimates were plotted.
In the multivariate approach, cox model was used for modeling survival times with all baseline characteristics.The proportionality of the hazards assumption in a Cox model was tested using Schoenfeld residuals.We also performed a log rank analysis in critically ill patients to assess signi cance of systemic steroids.Statistical analyses were performed with the use of STATA software version 14.2.

Results
1173 patients met the study criteria and were included in nal analysis (Fig. 1).Of these, 837 (71.4%) patients never smoked and 336 (28.6%) were either current smokers or had smoked in the past.There was no difference between the smokers and non-smokers with regards to age or body mass index (BMI).
Median survival was 14 days (95% con dence interval 12-17 days) in smokers and 16 days (95% con dence interval 14-18 days) in non-smokers, which was statistically signi cant (Table 2).Cox model for survival analysis by smoking status showed that hazard ratio for smokers was 1.34 suggesting that this group have the risk of death 34% higher than non-smokers (Fig. 2).When the analysis was repeated with smokers subdivided into current smokers and past smokers, hazard ratio for smokers was 1.615 suggesting that this group have the risk of death 61.5% higher than non-smokers.

Role of Systemic Steroids
A total of received systemic steroids.Of these, 235 patients were critically ill, 72 had severe illness, 84 had moderate illness and 35 patients had mild COVID-19 related illness.To compare the survival times log-rank test was used for severely ill and critically ill patients.Additionally, the Kaplan Meier estimates were plotted.No signi cant differences in outcomes were observed for severely ill patients p = 0.2903 (Fig. 4).In critically ill patients, analysis revealed that median survival time was 13 days (95% con dence interval 12-14 days) for patients who received systemic steroids compared to 6 days (95% con dence interval 5-7 days) for those who did not (p < 0.0001) (Fig. 5).

Discussion
Our study evaluated the patients that were admitted to our institution during the heart of the COVID-19 pandemic.We looked at various data points and how they correlated to the severity of COVID-19 infection.We found a direct relationship between smoking and severity of illness as well as mortality.Our data suggests that patients who ever smoked in their lives, had risk of death 34% higher compared to never-smokers.This translated to median survival time of 14 days in smokers, which was statistically lower than never-smokers who had median survival of 16 days.We then subdivided smokers into current smokers and past smokers; we noticed that risk of death in current smokers was 61% higher compared to never smokers.When past smokers were compared with never smokers, we did not nd any statistical increase in risk of death.This nding is in contrast with the recently published literature that showed signi cant up-regulation of pulmonary ACE2 gene expression in both current and past smokers.The study suggested this up-regulation increased risk of viral binding and entry of the virus into the lungs of both current and past smokers. 9other signi cant nding of our study was that 28.6% of our patients had smoked at some point in their lives.This number is higher than what has been reported in the recent literature.In two meta-analyses, pooled prevalence of smokers in hospitalized patients was 7.6% (3.8-12.4%)and 6.5% (1.4% − 12.6%) 12,13 From calendar year 2012 to year 2016, New York City has seen a signi cant decrease in the percentage of adults who smoke. 10 This reduction has been attributed to comprehensive strategies that include media campaigns, smoke free air policies and increased access to cessation resources.
Nonetheless, 13.1% of the adult living in New York City still smoke cigarettes. 10In our study, 164 patients (13.9%) were current smokers which correlates with the prevalence data of the New York City.This nding may suggest that risk of getting hospitalized with COVID-19 illness is similar between smokers and general population.
Survival analysis further revealed that women were at lower risk of mortality than men (HR of 0.67), which is consistent with recently published data. 14While exact mechanism that confers protection to females is not known, a study showed that the circulating ACE2 levels are higher in men than in women. 15These ndings may suggest why men are at higher risk of developing serious COVID-19 illness.Increased age and serum LDH levels were also shown to be independently associated with survival.In addition, our data showed that patients who received systemic steroids were more likely to survive.
Upon further analysis, this nding was not signi cant for severely ill patients.Critically ill patients showed signi cant survival advantage with use of systemic steroids.Systemic steroids in COVID-19 have been much of controversy.Guidelines issued by World Health Organization on March 13th 2020 had advised to avoid routine use system steroids for treatment of viral pneumonia. 16A literature review by Russel et al. went even further and stated that not only that the evidence does not support any bene t but there may even be harm if steroids are used in COVID-19 patients. 17Wu et al. subsequently published their ndings in a subgroup of COVID-19 patients who developed ARDS. 18Their study showed that patients who received methylprednisolone were more likely to survive compared to those who did not.This study was one of the key considerations when our institutional protocol suggested the use of systemic steroids in select subgroup of patients hospitalized with COVID-19.Our results con rm the ndings by Wu et al. in suggesting bene ts of systemic steroids use in critically ill patients.
Our study has several limitations.First, this is a single center, retrospective study, and therefore at risk of selection bias.Second, as this study includes patients that were admitted during the COVID-19 crisis, many of whom were seriously ill to provide detailed history, data was limited with regards to pack year smoking as well as how long ago past smokers quit smoking.Third, we did not account for other inhaled recreational agents such as marijuana.Our ndings need further con rmation in a larger prospective cohort.

Conclusion
Our study ndings suggest that smoking is associated with higher likelihood of developing critical illness and higher likelihood of death in patients hospitalized with COVID-19 illness.Use of systemic steroids in critically ill patients was independently associated with improved survival.

Table 1
Baseline demographics of smokers and never-smokers.N = number of patients.

Table 2
Comparison of the various in-hospital therapies and outcomes between smokers and never-smokers

Table 3
Univariate Cox Model for Smoking and SurvivalIn the multivariate approach Cox model for the survival, the signi cant effects were observed for female sex, age, LDH and systemic steroid use.HR for age was equal 1.02, which indicated the risk of death increasing by 2% with every additional year of age of the patient at baseline.HR for systemic steroids was equal to 0.42, which indicates the risk of death smaller by 58% for patients taking systemic steroids.HR for female gender was equal 0.75, which indicates the risk of death smaller by 25%.HR for LDH was equal 1.0005 that indicated the increase of 0.05% in the risk of death by every additional unit of LDH (Table4).
Abbreviations: CI; con dence interval, HR; hazard ratio, LDH; lactate dehydrogenase This study was approved by the institutional review board at Bronxcare Health System under an expedited review in the setting of a global pandemic (IRB # 06 11 20 09).Need for consent was waived due to retrospective nature of the study.