Association of Smoking and Cumulative Pack-Year Exposure With COVID-19 Outcomes in the Cleveland Clinic COVID-19 Registry | Critical Care Medicine | JAMA Internal Medicine | JAMA Network
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Table 1.  Demographics of Patients Who Tested Positive for COVID-19 Within the Cleveland Clinic Health System
Demographics of Patients Who Tested Positive for COVID-19 Within the Cleveland Clinic Health System
Table 2.  Logistic Regression Models for COVID-19 Outcomes by Smoking Status Among the Cohort
Logistic Regression Models for COVID-19 Outcomes by Smoking Status Among the Cohort
1.
Patanavanich  R, Glantz  SA.  Smoking is associated with COVID-19 progression: a meta-analysis.   Nicotine Tob Res. 2020;22(9):1653-1656. doi:10.1093/ntr/ntaa082PubMedGoogle ScholarCrossref
2.
Berlin  I, Thomas  D, Le Faou  AL, Cornuz  J.  COVID-19 and smoking.   Nicotine Tob Res. 2020;22(9):1650-1652. doi:10.1093/ntr/ntaa059PubMedGoogle ScholarCrossref
3.
Guan  WJ, Ni  ZY, Hu  Y,  et al; China Medical Treatment Expert Group for Covid-19.  Clinical characteristics of coronavirus disease 2019 in China.   N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032PubMedGoogle ScholarCrossref
4.
Luo  J, Rizvi  H, Preeshagul  IR,  et al.  COVID-19 in patients with lung cancer.   Ann Oncol. 2020;31(10):1386-1396. doi:10.1016/j.annonc.2020.06.007PubMedGoogle ScholarCrossref
5.
Mehta  N, Kalra  A, Nowacki  AS,  et al.  Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19).   JAMA Cardiol. 2020;5(9):1020-1026. doi:10.1001/jamacardio.2020.1855PubMedGoogle ScholarCrossref
6.
Price-Haywood  EG, Burton  J, Fort  D, Seoane  L.  Hospitalization and mortality among black patients and white patients with Covid-19.   N Engl J Med. 2020;382(26):2534-2543. doi:10.1056/NEJMsa2011686PubMedGoogle ScholarCrossref
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    3 Comments for this article
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    Cumulative pack-year somking is the high risk of COVID-19
    Jianshe Yang, PhD, MSc | Shanghai Tenth People's Hospital, Tongji University, China
    Jianshe Yang﹡, PhD, MSc, Chengyou Jia, MD
    Shanghai Tenth People’s Hospital, Tongji University, Shanghai 200072, China

    ﹡Correspondence to: Jianshe Yang, Professor of Shanghai Tenth People’s Hospital, Tongji University, China.
    Address: No.301, Yanchang Road (middle), Jingan District, Shanghai 200072, China
    Tel: +86 21 66302721, Email: yangjs@impcas.ac.cn

    A cogent demonstration that increased cumulative smoking was associated with a higher risk of hospitalization and mortality from COVID-19 in a dose-dependent manner published on JAMA Internal Medicine [1] has raised our greatest concern.
    Undoubtedly the U.S. government and relevant organizations contribute the great efforts to cigarette control, as described in
    NEJM, [2] they coordinately established the excellent prevention and education system for help Americans quit smoking, and continue to improve it.
    It is human nature to seek advantages. To maintain good living habits is necessary, while, it is quite critical to take the severe smoking-induced consequences as a warning education. As described in this research letter 1, persons with no smoking history presented a significant good prognosis than that of pack-year smokers in case of infecting with SARS-CoV-2. It is urgently suggested to show the detailed dreaded pathological pictures publicly. Only by recognizing the terrible end of smoking can people really take the initiative to quit it. Furthermore, for smoking-cessation, it's essential to investigate the exact triggers that people use to smoking, because we know that people are more psychologically dependent on tobacco than physical aspects.
    Moreover, the outbreak of seasonal influenza or some occasional (but seems to be more and more frequent) highly pathogenic viruses, like SARS-CoV-2, is a huge burden on the respiratory system. Both direct and indirect evidence suggest that smoking exacerbates the outcome of these lung-dominated infectious diseases, and result in a higher mortality. [3,4]
    So, quitting smoking! The sooner the better!

    Disclosure
    The authors report no conflicts of interest in this work.
    References
    1.Lowe KE, Zein J, Hatipoğlu U, Attaway A. Association of Smoking and Cumulative Pack-Year
    Exposure With COVID-19 Outcomes in the Cleveland Clinic COVID-19 Registry. JAMA Intern Med. Published online January 25, 2021. doi:10.1001/jamainternmed.2020.8360
    2.Redfield RR, Hahn SM, Sharpless NE. Redoubling efforts to help Americans quit
    smoking-Federal Initiatives to tackle the country’s longest-running epidemic. N Eng J Med. 2020; 383:1606-1609.
    3.Patanavanich R, Glantz SA. Smoking is associated with COVID-19 progression: a meta-analysis. Nicotine Tob Res. 2020;22(9):1653-1656. doi:10.1093/ntr/ntaa082
    4.Berlin I, Thomas D, Le Faou AL, Cornuz J. COVID-19 and smoking. Nicotine Tob Res.
    2020;22(9):1650-1652. doi:10.1093/ntr/ntaa059
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Active smoking and cumulative pack-year exposure in COVID-19 patients
    Marco Rossato, MD, PhD | University Hospital of Padova, Padova, Italy
    Lowe et al. reported the role of the cumulative effect of smoking on the risk of hospitalization, intensive care unit (ICU) admission and death in SARS-CoV-2 positive subjects, showing that heavy smokers had 2.25 times higher odds of hospitalization and were 1.89 times more likely to die following a COVID-19 diagnosis with respect to never smokers.1 While the results on the risk of ICU admittance and death have been previously reported, being in agreement with the important cardiovascular co-morbidities affecting heavy smokers,2,3 the results on hospitalization are in contradiction with those reported by many recent published studies coming from different countries evidencing that among hospitalized patients for COVID-19 the prevalence of active smokers is quite low.2-5
    In their analysis, Lowe et al. considered active smokers and former smokers as a whole as derived by the analysis of Table I showing the number of patients considered in the different groups and in fact only never smokers have been considered as reference. It could be of interest to have the odds ratios for hospitalization, ICU admittance and death of current active smokers and former smokers taken separately, also considering that in this study the active smokers were only 172 (2.4%) and no active smokers (former and never smokers) 6930 (97.6%).1
    This is not trivial since the presence of active cigarette smoking (and whatever active molecule(s) present within smoke) has been suggested to be somehow “protective” on SARS-CoV-2 infection severe pulmonary complications.3,4 This is further strengthened by the recent observation that COVID-19 severity is related to past and not to current smoking history.5 Nonetheless, cigarette smoking has to be strongly discouraged given its important and well known unhealthy effects.
    Although the mechanisms by which active smoking exerts these “protective” effects are still debated,3,4 it is not disputable that among hospitalized patients with COVID-19 the active smokers are very few.2-5 Thus, while we agree with Lowe et al. that smokers (active and former) are at higher risk for ICU admittance and death with respect to never smokers due to their important cardiovascular an systemic co-morbidities, their conclusion that the risk of hospitalization of SARS-CoV-2 positive subjects is higher for smokers with respect to never smokers should be further examined.
    References
    1. Lowe KE, Zein J, Hatipoglu U, Attaway A. Association of Smoking and Cumulative Pack-Year Exposure With COVID-19 Outcomes in the Cleveland Clinic COVID-19 Registry. JAMA Intern Med. 2021 Jan 25. doi: 10.1001/jamainternmed.2020.8360
    2. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032
    3. Farsalinos K, Bagos PG, Giannouchos T, Niaura R, Barbouni A, Poulas K. Smoking prevalence among hospitalized COVID-19 patients and its association with disease severity and mortality: an expanded re-analysis of a recent publication. Harm Reduct J. 2021 ;18(1):9. doi: 10.1186/s12954-020-00437-5.
    4. Rossato M, Russo L, Mazzocut S, Di Vincenzo A, Fioretto P, Vettor R. Current smoking is not associated with COVID-19. Eur Respir J. 2020;55(6):2001290. doi: 10.1183/13993003.01290-2020
    5. Zhang T, Huang WS, Guan W, et al. Risk factors and predictors associated with the severity of COVID-19 in China: a systematic review, meta-analysis, and meta-regression. J Thorac Dis. 2020;12(12):7429-7441. doi: 10.21037/jtd-20-1743
    CONFLICT OF INTEREST: None Reported
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    COVID-19 and Smoking; Death Rate versus Age?
    Gary Ordog, MD, DABEM, DABMT | County of Los Angeles, Department of Health Services, (retired)
    Thank you for the very interesting paper. I am concerned, however, about a confounding variable. That is, "age." The never smokers" study group had a mean age of 47.8 years, and the "smokers" group had a mean age of 71 years. As mortality from COVID-19 increases with increasing age, this confounding variable should be controlled for, perhaps by matching the two study groups for age, and then comparing the outcome.
    CONFLICT OF INTEREST: None Reported
    Research Letter
    January 25, 2021

    Association of Smoking and Cumulative Pack-Year Exposure With COVID-19 Outcomes in the Cleveland Clinic COVID-19 Registry

    Author Affiliations
    • 1Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio
    • 2Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
    JAMA Intern Med. 2021;181(5):709-711. doi:10.1001/jamainternmed.2020.8360

    There is limited and contradictory evidence on the association of smoking status with adverse outcomes of severe acute respiratory syndrome coronavirus 2 infection.1-3 Furthermore, current smoking status does not encompass the cumulative effect of smoking. To our knowledge, no studies have assessed the cumulative effect of smoking over time, as measured by pack-years, though a single study of coronavirus disease 2019 (COVID-19) in a small cohort of 102 patients with lung cancer found that the patients with severe outcomes had a higher average pack-year history (30 vs 20 years).4 We hypothesize that there is an adverse association of cumulative smoking exposure, as measured by pack-years, with outcomes of patients with COVID-19.

    Methods

    The Cleveland Clinic initiated a COVID-19 registry starting on March 8, 2020, that includes all patients tested for COVID-19 within the Cleveland Clinic Health system in Ohio and Florida. Basic demographic information was collected during testing, including age, height, weight, self-reported gender, self-reported race, and select comorbidities. Additional data on comorbidities, medications, and outcomes were extracted from patient electronic medical records.5 The Cleveland Clinic Institutional Review Board approved this study and waived the need for patient informed consent owing to use of deidentified database information on study participants.

    Adults who tested positive for COVID-19 between March 8, 2020, and August 25, 2020, and who had full smoking information recorded were included in the cohort. We classified patients based on their cumulative recorded smoking exposure. Those who reported that they were never smokers were compared with patients reporting 0 to 10 pack-years, 10 to 30 pack-years, and more than 30 pack-years. Demographic differences between these groups and previous literature on the risk factors of adverse COVID-19 outcomes informed the study modeling.1,3,5,6 We used multivariable logistic regression models to determine the odds ratio for hospitalization given a positive test, admission to the intensive care unit given hospitalization, and death given a positive COVID-19 test for each pack-year cohort compared with never smokers. Regression models were run unadjusted, adjusted for identified confounders (age, race, and gender) and adjusted for mediators (adding coronary artery disease, hypertension, chronic obstructive pulmonary disease, diabetes, use of angiotensin receptor blockers, and use of oral or inhaled corticosteroids). We used likelihood ratio tests to determine whether a given covariate would remain in the model.

    Results

    Of the 7102 patients included in the cohort, 6020 (84.8%) were never smokers, 172 (2.4%) were current smokers, and 910 (12.8%) were former smokers. All demographics are summarized in Table 1, and the results of logistic regression analyses are summarized in Table 2. The findings showed a dose-response association between pack-years and adverse COVID-19 outcomes. Patients who smoked more than 30 pack-years had a 2.25 times higher odds of hospitalization (95% CI, 1.76-2.88), and these heavy smokers were 1.89 times more likely to die following a COVID-19 diagnosis (95% CI, 1.29-2.76) when compared with never smokers. The association between cumulative smoking and adverse COVID-19 outcomes is likely mediated in part by comorbidities. The odds ratios for all adverse outcomes were attenuated in the mediation models. There was no evidence of effect modification by smoking status; similar odds ratios were seen in both current and former smokers.

    Discussion

    The results of this study suggest that cumulative exposure to cigarette smoke is an independent risk factor for hospital admission and death from COVID-19. Smoking is imperfectly classified in patient electronic medical records, and former smokers are potentially classified as never smokers, while pack-years may be underrecorded. However, this misclassification is likely to bias the present results toward the null, which would underestimate the association of cigarette smoking on adverse COVID-19 outcomes. The limitations on who has access to care at tertiary medical centers in the United States prevent generalizability to the whole population. The patients with complete data in this study are likely to be wealthier and have more consistent access to health care, as pack-years of smoking was typically collected during previous visits to the Cleveland Clinic. Nevertheless, we have demonstrated in this single central registry of patients who tested positive for COVID-19 that increased cumulative smoking was associated with a higher risk of hospitalization and mortality from COVID-19 in a dose-dependent manner.

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    Article Information

    Accepted for Publication: November 7, 2020.

    Published Online: January 25, 2021. doi:10.1001/jamainternmed.2020.8360

    Correction: This article was corrected on March 8, 2021, to fix a data error in the Results section.

    Corresponding Author: Katherine E. Lowe, MSc, Cleveland Clinic Lerner College of Medicine of Case Western Reserve, 9501 Euclid Ave, Cleveland, OH 44195 (lowek@ccf.org).

    Author Contributions: Ms Lowe had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Lowe, Hatipoğlu, Attaway.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Lowe, Zein, Attaway.

    Administrative, technical, or material support: Hatipoğlu

    Supervision: Zein, Hatipoğlu, Attaway.

    Conflict of Interest Disclosures: Dr Hatipoğlu reports receiving royalties from Wolters Kluwer Health for his work as section editor for UpToDate. No other disclosures were reported.

    Funding/Support: Research support was provided through a grant from the National Institutes of Health’s National Heart, Lung, and Blood Institute (K08HL133381).

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Patanavanich  R, Glantz  SA.  Smoking is associated with COVID-19 progression: a meta-analysis.   Nicotine Tob Res. 2020;22(9):1653-1656. doi:10.1093/ntr/ntaa082PubMedGoogle ScholarCrossref
    2.
    Berlin  I, Thomas  D, Le Faou  AL, Cornuz  J.  COVID-19 and smoking.   Nicotine Tob Res. 2020;22(9):1650-1652. doi:10.1093/ntr/ntaa059PubMedGoogle ScholarCrossref
    3.
    Guan  WJ, Ni  ZY, Hu  Y,  et al; China Medical Treatment Expert Group for Covid-19.  Clinical characteristics of coronavirus disease 2019 in China.   N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032PubMedGoogle ScholarCrossref
    4.
    Luo  J, Rizvi  H, Preeshagul  IR,  et al.  COVID-19 in patients with lung cancer.   Ann Oncol. 2020;31(10):1386-1396. doi:10.1016/j.annonc.2020.06.007PubMedGoogle ScholarCrossref
    5.
    Mehta  N, Kalra  A, Nowacki  AS,  et al.  Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19).   JAMA Cardiol. 2020;5(9):1020-1026. doi:10.1001/jamacardio.2020.1855PubMedGoogle ScholarCrossref
    6.
    Price-Haywood  EG, Burton  J, Fort  D, Seoane  L.  Hospitalization and mortality among black patients and white patients with Covid-19.   N Engl J Med. 2020;382(26):2534-2543. doi:10.1056/NEJMsa2011686PubMedGoogle ScholarCrossref
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