1173 patients met the study criteria and were included in final 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). Males and African Americans were more likely to be smokers. Smokers had higher incidence of COPD (19% vs. 6%, p < 0.001), human immunodeficiency 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 (Table 1). Admission D-dimer, lactate dehydrogenase (LDH), absolute neutrophil count (ANC), absolute lymphocyte count (ALC) and C-reactive protein (CRP), ferritin, serum lactate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, serum albumin, hemoglobin, mean corpuscular hemoglobin concentration, white blood cell count, serum sodium and serum potassium levels were similar between the two groups. Smokers had higher serum creatinine (1.2 mg/dl vs. 1.0 mg/dl, p = 0.0144) and higher mean corpuscular volume (89.16 vs 88, p = 0.008) compared to non-smokers. There was no difference between the two groups with regards to chest x-ray or computed tomography findings.
Table 1
Baseline demographics of smokers and never-smokers. N = number of patients.
| Smokers N = 336 | Never-Smokers N = 837 | P value |
Age, years – median (IQR) | 64 (54–73) | 62 (52–73) | 0.296 |
Sex - no (%) Female Male | 87 (26%) 249 (74%) | 366 (44%) 471 (56%) | < 0.001 |
Ethnicity – no (%) Hispanic Black Caucasian Others | 183 (54%) 114 (34%) 10 (3%) 29 (9%) | 548 (66%) 206 (25%) 6 (1%) 77 (9%) | < 0.001 |
BMI – median (IQR)* | 28.6 (24.4–33.1) | 28.9 (25.8–33.7) | 0.693 |
Comorbidities – no (%) Hypertension Diabetes mellitus HIV infection/AIDS Asthma COPD Chronic Liver Disease Any Cancer Congestive heart failure Coronary artery disease Chronic kidney disease ESRD | 213 (63.4%) 158 (47%) 37 (11%) 52 (16%) 64 (19%) 5 (1.5%) 36 (11%) 50 (15%) 49 (15%) 38 (11%) 35 (10%) | 524 (63%) 377 (45%) 39 (5%) 111 (13%) 49 (6%) 6 (1%) 50 (6%) 66 (8%) 78 (9%) 63 (8%) 64 (6%) | 0.819 0.683 < 0.001 0.624 < 0.001 0.381 0.005 < 0.001 0.027 0.037 0.009 |
Initial laboratory tests – median (IQR)* | | | |
Absolute neutrophil count (ANC) (k/ul) | 5.7 (3.7–8) | 6.0 (4.1–8.3) | 0.256 |
Absolute lymphocyte count (ALC) (k/ul) | 0.8 (0.5–1.3) | 0.9 (0.6–1.2) | 0.692 |
ANC/ALC ratio | 6.6 (4.0–11.6) | 6.8 (4.3–11.4) | 0.488 |
D-dimer (ng/ml) | 536 (317–1025) | 533 (304–1254) | 0.945 |
Lactate Dehydrogenase (u/L) | 490 (308–741) | 483(350–690) | 0.633 |
C-reactive protein (mg/L) | 104.3 (46.6–181.4) | 117.65 (62.42–198.70) | 0.232 |
Ferritin (ng/ml) | 752.6 (328.8–1466.5) | 700.1 (364.6–1380.5) | 0.402 |
Lactate (mmoles/L) | 1.8 (1.3–2.55) | 1.8 (1.3–2.5) | 0.404 |
Creatinine (mg/dl) | 1.2 (0.9–2.07) | 1.0 (0.8–1.6) | < 0.001 |
Alanine Aminotransferase (unit/L) | 29 (18–49) | 29 (18–48) | 0.986 |
Aspartate Aminotransferase (unit/L) | 49 (30–78) | 46 (31–71.5) | 0.056 |
Total Protein (g/dl) | 6.9 (6.5–7.6) | 7.0 (6.5–7.5) | 0.668 |
Serum Albumin (g/dl) | 3.6 (3.2–4) | 3.6 (3.3–3.9) | 0.667 |
Hemoglobin (g/dl) | 13.2 (11.7–14.6) | 13.2 (11.8–14.5) | 0.893 |
White blood cell (k/ul) | 7.3 (5.3–9.8) | 7.5 (5.5–10.2) | 0.321 |
Mean corpuscular volume (fL) | 89.15 (84.9–93.1) | 88 (83.7–91.7) | 0.008 |
Mean corpuscular hemoglobin (pg) | 33.4 (32.6–34.0) | 33.3 (32.5–34.0) | 0.243 |
Serum Sodium (mEq/L) Serum Potassium (mEq/L) | 136 (133–139) 4.5 (4.1–5.0) | 137 (133–139) 4.4 (4.0–4.9) | 0.376 0.150 |
Chest x-ray (CXR) Normal Alveolar/interstitial infiltrates Pleural effusion | 46 (14%) | 96 (11%) | 0.248 |
281 (85%) | 727 (88%) | |
5 (1%) | 6 (1%) | |
CT chest Normal Alveolar/interstitial infiltrates Pleural effusion | 0 | 3(2%) | 0.186 |
52 (96%) | 133 (97%) | |
2 (4%) | 1 (1%) | |
*Mean and SD not provided since normality assumption violated |
Abbreviations: COPD: chronic obstructive pulmonary disease, ESRD: end stage renal disease, k/ul: cubic milimter, fl; femtoliter, g/dl; gram per deci liter mEq/L: miliequivalents per liter, mg/dl: milligram per deciliter, mg/L: milligram per liter, mmol/l: milli mole per liter, ng/ml: nannogram per milliliter, pg; pico gram, SD: standard deviation, unit/L: unit per liter |
Evaluating the in-patient treatment, smokers were more likely to develop critical illness requiring mechanical ventilation (47% vs. 37% p = 0.005). Use of hydroxychloroquine, anti-retrovirals, systemic steroids was similar between the two group whereas Tocilizumab use was higher in non-smokers.
Median survival was 14 days (95% confidence interval 12–17 days) in smokers and 16 days (95% confidence interval 14–18 days) in non-smokers, which was statistically significant (Table 2).
Table 2
Comparison of the various in-hospital therapies and outcomes between smokers and never-smokers
| Smokers N = 336 | Never-Smokers N = 837 | P value |
Oxygen Therapy None Low flow oxygen High flow oxygen Invasive mechanical ventilation | 36 (11%) 102 (30%) 39 (12%) 159 (47%) | 126 (15%) 278 (33%) 126 (15%) 307 (37%) | 0.005 |
Medications Hydroxychloroquine Anti-retrovirals Steroids Tocilizumab | 243 (72%) 38(11%) 114 (34%) 17 (5%) | 624 (75%) 81 (10%) 304 (36%) 85 (10%) | 0.432 0.677 0.439 0.005 |
Severity of illness Mild (0) Moderate (1) Severe (2) Critical (3) | 6 (2%) 30 (9%) 141 (42%) 159 (47%) | 11 (1%) 115 (14%) 404 (48%) 307 (37%) | 0.003 |
Survival time (days) | Median survival = 14 95%CI = 12–17 days | Median survival = 16 95%CI = 14–18 days | 0.0050 |
Of the 336 smokers, 172 (51.2%) were past smokers and 164 (48.8%) were current smokers. Univariate 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.
Survival for the past smokers was similar to non-smokers (HR 1.14, 95% confidence interval 0.8739–1.5125) (Fig. 3) (Table 3).
Table 3
Univariate Cox Model for Smoking and Survival
Risk Factors | Hazard Ratio (HR) (95% CI for HR) | p value |
Current and Past Smoker | 1.34 (1.08–1.66) | 0.006 |
Current Smoker | 1.61 (1.22–2.12) | 0.001 |
Past Smoker | 1.14 (0.87–1.51) | 0.319 |
Abbreviations: CI; confidence interval, HR; hazard ratio |
In the multivariate approach Cox model for the survival, the significant 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 (Table 4).
Table 4
Multivariate Cox Model for Survival
Parameter | Hazard Ratio (HR) (95% CI for HR) | p value |
Female Gender | 0.67 (0.53–0.84) | 0.001 |
Age | 1.02 (1.02–1.03) | < 0.001 |
Admission LDH | 1.00 (1.00–1.00) | < 0.001 |
Systemic Steroids | 0.62 (0.49–0.77) | < 0.001 |
Abbreviations: CI; confidence interval, HR; hazard ratio, LDH; lactate dehydrogenase |
Role of Systemic Steroids
A total of 418 patients 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 significant 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% confidence interval 12–14 days) for patients who received systemic steroids compared to 6 days (95% confidence interval 5–7 days) for those who did not (p < 0.0001) (Fig. 5).