Smoking may increase the risk of influenza hospitalization and reduce influenza vaccine effectiveness in the elderly

Smoking may increase the risk of influenza hospitalization and reduce influenza vaccine... Abstract Background Through its effects on the immune system, smoking may facilitate influenza virus infection, its severity and its most frequent complications. The objective was to investigate the smoking history as a risk factor for influenza hospitalization and influenza vaccine effectiveness in elderly smokers/ex-smokers and non-smokers. Methods We carried out a multicenter case–control study in the 2013–2014 and 2014–2015 influenza seasons. Cases aged ≥65 years and age-, sex-matched controls were selected from 20 Spanish hospitals. We collected epidemiological variables, comorbidities, vaccination history and the smoking history. The risk of hospitalization due to smoking (current smokers and ex-smokers) was determined using the adjusted odds ratio (aOR) with conditional logistic regression models. Vaccine effectiveness (VE) was calculated using the formula: VE = (1 – aOR) × 100. Results We studied 728 cases and 1826 controls. Cases had a higher frequency of smoking (47.4% vs 42.1%). Smoking was associated with an increased risk of influenza hospitalization (aOR = 1.32, 95% CI: 1.04–1.68). Influenza vaccine effectiveness in preventing hospitalization was 21% (95% CI: -2 to 39) in current/ex-smokers and 39% in non-smokers (95% CI: 22–52). Conclusions A history of smoking may increase the risk of hospitalization in smokers and ex-smokers. Preventing smoking could reduce hospitalizations due to influenza. Smokers and ex-smokers should be informed of the risk of hospitalization due to influenza infection, and encouraged to stop smoking. Smokers should be considered an at-risk group to be aggressively targeted for routine influenza vaccination. Introduction Influenza affects a large percentage of the population each year, with estimates as high as 15%.1 The smoking prevalence of 30.5% in men and 20.5% in woman found in the Spanish population according to the latest National Health Survey remains very high,2 but is lower in the elderly (16.2% in men and 4.6% in woman aged 65–74 years). Smoking favors the frequency and severity of several respiratory diseases.3 Tobacco smoke causes the deposition of particles in the airways that damage the protection mechanisms of the respiratory system at different levels, alters the function of the ciliary mucus and the clearance of inhaled substances, enables the adherence of bacteria to airway epithelial cells, increases alveolar permeability and decreases cellular and humoral immunity.4,5 Through these effects on the immune system, smoking may facilitate influenza virus infection, its severity, and its most frequent complications, such as bacterial pneumonia.6,7 Studies have estimated that smokers have more than twice the risk of clinical disease8,9 compared with non-smokers and also present more severe forms.10 Some authors suggest that these effects are dependent on the chronicity of smoking and may persist, although to a lesser extent, after stopping smoking.11–13 The presence of concomitant diseases strongly associated with smoking, such as chronic obstructive pulmonary disease (COPD) and congestive heart disease, make it difficult to assess the role of smoking in increasing the severity of influenza.14,15 The role of smoking in influenza in the elderly may be more difficult to assess due to the lower prevalence of smokers and the higher prevalence of ex-smokers and because some smokers die before the age of 65 years due to tobacco-related causes.16 Thus, there is a need to determine the effect of smoking as a risk factor for influenza hospitalization in the elderly. The aim of this study was to estimate the smoking history as a risk factor for influenza hospitalization and influenza vaccine effectiveness in smokers/ex-smokers and non-smokers in the 2013–2014 and 2014–2015 influenza seasons in Spain in people aged ≥65 years. Methods Study design We designed a multicenter, case–control study in 20 Spanish hospitals from seven Spanish regions (Andalusia, the Basque Country, Castile and Leon, Catalonia, Madrid, Navarre and Valencia Community). All were public reference hospitals located in the main cities of each community and all provided free-at-the-point-of-delivery healthcare under the auspices of the Spanish National Health Service. Cases hospitalized due to influenza in the participating hospitals in the 2013–2014 and 2014–2015 influenza seasons and corresponding inpatient controls were recruited. Selection of cases and controls Patients aged ≥65 years hospitalized for at least 24 h with laboratory-confirmed influenza virus infection [reverse-transcription polymerase chain reaction (RT-PCR), culture or immunofluorescence] were selected. Patients with nosocomial infection, defined as influenza virus infection appearing ≥ 48 h after admission for other reasons, were excluded. Three matched controls were selected for each case from patients aged ≥65 years with unplanned hospital admission due to causes other than influenza or acute respiratory disease. Controls were matched with each case according to age (±3 years), sex and date of hospitalization (±10 days). Controls were selected from patients admitted to the general surgery, internal medicine service, ophthalmology, otorhinolaryngology, dermatology, or traumatology services. Patients referred from nursing homes and those who did not provide written informed consent were excluded. Data collection Hospitalized cases and controls were interviewed by specifically-trained health professionals using the same structured questionnaire at a similar time after hospitalization and their medical records were reviewed. The following demographic variables and pre-existing medical conditions were recorded: age, sex, marital status, educational level, smoking and alcohol intake, the Barthel index as a measurement of limitations in activity (ranging from 0—complete dependence to 100—complete independence), COPD, chronic respiratory failure, history of pneumonia during the last two years, other lung diseases, neoplasia, transplantation, diabetes, renal failure, congestive heart disease, disabling neurological disease, obesity [body mass index (BMI) ≥ 30] and chronic liver disease. Definition We defined the variable ‘Any risk medical condition’ as: Yes (≥1: COPD, congestive heart disease, renal failure, diabetes, chronic liver disease) or No (no risk medical conditions). High alcohol consumption as: Yes (>40 g/day for men and >24 g/day for women) or No. Smoking was defined as habitual smoker (any smoking in the last 6 months), ex-smoker (former smoker who gave up and had not smoked in the last 6 months) and never smoker. As the prevalence of smokers was very low, we combined smoker and ex-smoker in the same category for the analysis. Information on the seasonal influenza vaccine status and pneumococcal vaccination status was obtained from medical records or vaccination cards. Cases and controls were considered vaccinated with the seasonal influenza vaccine if they had received a dose of the trivalent inactivated vaccine at least 14 days before the onset of symptoms of the case. Statistical analysis A bivariate comparison was made between cases and controls for demographic variables, smoking, alcohol intake, Barthel index, influenza vaccine and any medical conditions using the McNemar test for categorical variables. Unadjusted matched odds ratios (OR) were estimated using the McNemar test. Multivariate analysis using conditional logistic regression was made to estimate the adjusted OR (aOR) for smoking status (smokers and ex-smokers). Covariates were introduced into the model using a backward stepwise procedure, with a cut-off point of P < 0.2. In the different regression models, the aOR for smoking for all cases and controls considered together and by sex and age-group (65–74; 75–84; and ≥85 years) were calculated to evaluate possible differences and rule out selection bias. The analysis according to sex or age group was adjusted using conditional logistic regression. The effect of the vaccine was evaluated according to the smoking categories (smokers/ex-smokers and nonsmokers) using unconditional logistic regression with backward selection of variables, with a cut-off point of P < 0.2. Vaccine effectiveness (VE) was calculated using the formula: VE = (1 – aOR) × 100. The fraction of influenza hospitalization attributable to smoking in the exposed population was calculated by estimating the attributable risk in the exposed population: (ARe) = [(aOR–1)/(aOR–1) + 1] × 100. The analysis was performed using the SPSS v.23 statistical package and the R v3.3.0 statistical software (http://cran.r-project.org). Ethical considerations All data collected were treated as confidential, in strict observance of legislation on observational studies. The study was approved by the Ethics Committees of the participating hospitals. Written informed consent was obtained from all patients included in the study. Results We studied 728 cases with RT-PCR-confirmed influenza (443 cases from season 2013–2014 and 295 from season 2014–2015) and 1826 controls. Cases and controls had a similar frequency of females (47.1% vs 48.4%), and patients in each age group (P = 0.29) (Table 1). However, compared with controls, cases had a different distribution of the marital status (P = 0.02) and the Barthel index (P = 0.08), a lower prevalence of influenza vaccination (49.3% vs 57.7%; P < 0.001) and a higher frequency of smoking (47.4% vs 42.1%; P = 0.01) (Table 1). The proportion of ex-smokers and current smokers was 39.6% and 7.8% in cases vs 35.0% and 7.1% in controls. Table 1 Distribution of cases and controls according to demographic variables, medical conditions and vaccination history Characteristics  Cases  Controls  P-value  (N = 728)  (N = 1826)  Smoking status            Smoker  57 (7.8%)  130 (7.1%)        Ex-smoker  288 (39.6%)  639 (35.0%)        Smoker/ex-smoker  345 (47.4%)  769 (42.1%)        Non smoker  383 (52.6%)  1057 (57.9%)  0.01  Age group            65–74 years  248 (34.1%)  614 (33.6%)        75–84 years  340 (46.7%)  883 (48.4%)        ≥85 years  140 (19.2%)  329 (18.0%)  0.29  Sex            Female  343 (47.1%)  884 (48.4)        Male  385 (52.9%)  942 (51.6%)  1.00  Marital status            Married/cohabiting  450 (61.9%)  1020 (56.0%)        Single  39 (5.4%)  145 (8.0%)        Widowed  217 (29.8%)  615 (33.8%)        Separated/divorced  21 (2.9%)  42 (2.3%)  0.02  Barthel index            0–60  123 (16.9%)  336 (20.1%)  0.08      >60  605 (83.1%)  1458 (70.9%)    High alcohol consumption            Yes  16 (2.2%)  53 (2.9%)        No  712 (97.8%)  1772 (97.1%)  0.38  Risk medical conditions            Yes  507 (69.6%)  1217 (66.6%)        No  221 (30.4%)  609 (33.4%)  0.04  Influenza vaccine            Yes  359 (49.3%)  1053 (57.7%)  <0.001      No  369 (50.7%)  773 (42.3%)    Pneumococcal vaccine            Yes  372 (51.1%)  836 (45.8%)  0.06      No  356 (48.9%)  990 (54.2%)    Characteristics  Cases  Controls  P-value  (N = 728)  (N = 1826)  Smoking status            Smoker  57 (7.8%)  130 (7.1%)        Ex-smoker  288 (39.6%)  639 (35.0%)        Smoker/ex-smoker  345 (47.4%)  769 (42.1%)        Non smoker  383 (52.6%)  1057 (57.9%)  0.01  Age group            65–74 years  248 (34.1%)  614 (33.6%)        75–84 years  340 (46.7%)  883 (48.4%)        ≥85 years  140 (19.2%)  329 (18.0%)  0.29  Sex            Female  343 (47.1%)  884 (48.4)        Male  385 (52.9%)  942 (51.6%)  1.00  Marital status            Married/cohabiting  450 (61.9%)  1020 (56.0%)        Single  39 (5.4%)  145 (8.0%)        Widowed  217 (29.8%)  615 (33.8%)        Separated/divorced  21 (2.9%)  42 (2.3%)  0.02  Barthel index            0–60  123 (16.9%)  336 (20.1%)  0.08      >60  605 (83.1%)  1458 (70.9%)    High alcohol consumption            Yes  16 (2.2%)  53 (2.9%)        No  712 (97.8%)  1772 (97.1%)  0.38  Risk medical conditions            Yes  507 (69.6%)  1217 (66.6%)        No  221 (30.4%)  609 (33.4%)  0.04  Influenza vaccine            Yes  359 (49.3%)  1053 (57.7%)  <0.001      No  369 (50.7%)  773 (42.3%)    Pneumococcal vaccine            Yes  372 (51.1%)  836 (45.8%)  0.06      No  356 (48.9%)  990 (54.2%)    The prevalence of smoking among cases was 58.9% in the 65–74 years age group, 45.6% in the 75–84 years age group and 31.4% in the ≥85 years age group; 75.3% in males vs 16.0% in females (P < 0.001); 66.7% in separated/divorced people, 59.0% in single people, 54.0% in married/cohabiting subjects and 29.5% in widowed persons; 51.2% in patients with a higher Barthel index vs 28.5% in those without (P < 0.001); 81.3% in patients with high alcohol consumption vs 46.6% in those without (P < 0.001); and 52.7% in persons with any risk medical condition vs 35.3% in those without (P < 0.001) (Table 2). Controls had a lower prevalence of smoking than cases although the patterns and differences within groups were similar (Table 2). In addition, the prevalence of smoking in non-vaccinated controls was 45.1% compared with 39.9% in vaccinated controls (P = 0.02) (Table 2). Table 2 Distribution of smoking status in cases and controls according to demographic variables, medical conditions and vaccination history   Smoking/total, n/N (%)  Characteristics  Cases  P-value  Controls  P-value  Total  345/728 (47%)    769/1826 (42%)    Age group              65–74 years  146 (58.9%)    329 (53.6%)        75–84 years  155 (45.6%)    367 (41.6%)        ≥85 years  44 (31.4%)  <0.001  73 (22.2%)  <0.001  Sex              Female  55 (16.0%)    82 (9.3)        Male  290 (75.3%)  <0.001  687 (72.9%)  <0.001  Marital status              Married/cohabiting  243 (54.0%)    521 (51.0%)        Single  23 (59.0%)    66 (45.5%)        Widowed  64 (29.5%)    151 (24.6%)        Separated/divorced  14 (66.7%)  <0.001  31 (73.8%)  <0.001  Barthel index              0–60  35 (28.5%)    128 (35.0%)        >60  310 (51.2%)  <0.001  641 (43.9%)  <0.001  High alcohol consumption              No  332 (46.6%)    721 (40.7%)        Yes  13 (81.3%)  <0.001  48 (90.6%)  <0.001  Risk medical conditions              Yes  267 (52.7%)    579 (47.6%)        No  78 (35.3%)  <0.001  190 (31.2%)  <0.001  Influenza vaccine              Yes  175 (48.7%)    420 (39.9%)        No  170 (46.1%)  0.47  349 (45.1%)  0.02  Pneumococcal vaccine              Yes  180 (48.4%)    328 (39.2%)        No  165 (46.3%)  0.58  441 (44.5%)  0.02    Smoking/total, n/N (%)  Characteristics  Cases  P-value  Controls  P-value  Total  345/728 (47%)    769/1826 (42%)    Age group              65–74 years  146 (58.9%)    329 (53.6%)        75–84 years  155 (45.6%)    367 (41.6%)        ≥85 years  44 (31.4%)  <0.001  73 (22.2%)  <0.001  Sex              Female  55 (16.0%)    82 (9.3)        Male  290 (75.3%)  <0.001  687 (72.9%)  <0.001  Marital status              Married/cohabiting  243 (54.0%)    521 (51.0%)        Single  23 (59.0%)    66 (45.5%)        Widowed  64 (29.5%)    151 (24.6%)        Separated/divorced  14 (66.7%)  <0.001  31 (73.8%)  <0.001  Barthel index              0–60  35 (28.5%)    128 (35.0%)        >60  310 (51.2%)  <0.001  641 (43.9%)  <0.001  High alcohol consumption              No  332 (46.6%)    721 (40.7%)        Yes  13 (81.3%)  <0.001  48 (90.6%)  <0.001  Risk medical conditions              Yes  267 (52.7%)    579 (47.6%)        No  78 (35.3%)  <0.001  190 (31.2%)  <0.001  Influenza vaccine              Yes  175 (48.7%)    420 (39.9%)        No  170 (46.1%)  0.47  349 (45.1%)  0.02  Pneumococcal vaccine              Yes  180 (48.4%)    328 (39.2%)        No  165 (46.3%)  0.58  441 (44.5%)  0.02  In the multivariate analysis, smoking (aOR = 1.32, 95% CI: 1.04–1.68) was significantly associated with the risk of influenza hospitalization (P = 0.02) (Table 3). In the logistic regression models according to age groups, the aOR between smoking and influenza hospitalization was > 1 in all age groups, but was only statistically significant in the ≥85 years age group (aOR = 2.27, 95% CI: 1.16–4.44) due to the low power of the estimates. Analysis by sex showed that the aOR for influenza hospitalization were all > 1, but were higher in females (aOR = 1.95, 95% CI: 1.28–2.97) than in males (aOR = 1.14, 95% CI: 0.85–1.52) (Supplementary Table). The fraction of the risk of influenza hospitalization attributable to smoking was 24.2% (95% CI: 3.84% to -410.5%) in current smokers/ex-smokers. Table 3 Smoking status (smoker and ex-smoker) as a risk factor for hospitalization in patients aged ≥ 65 years with laboratory-confirmed influenza in the regression model Characteristics  Crude OR (95% CI)  P-value  Adjusted OR (95% CI)  P-value  Smoking status              Smoker/ex-smoker  1.39 (1.09–1.77)  0.01  1.32 (1.04–1.68)  0.02      Non smoker  1    1    Age group              65–74 years  1    1        75–84  0.85 (0.57–1.27)  0.42  0.87 (0.57–1.32)  0.76      ≥85 years  1.13 (0.63–2.00)  0.69  1.28 (0.71–2.32)  0.42  Marital status              Married/cohabiting  1    1        Single  0.57 (0.39–0.83)  0.004  0.54 (0.36–0.79)  0.001      Widowed  0.76 (0.61–0.95)  0.02  0.73 (0.58–0.92)  0.007      Separated/divorced  1.17 (0.68–2.00)  0.57  1.13 (0.66–1.95)  0.66  Barthel index              >60  1.25 (0.97–1.60)  0.08  1.31 (1.02–1.70)  0.03      0–60  1    1    Any medical conditions              High risk  1.23 (1.01–1.50)  0.04  1.27 (1.04–1.56)  0.02      Non high risk  1    1    Influenza vaccination              Yes  0.73 (0.61–0.87)  <0.001  0.70 (0.58–0.83)  <0.001      No  1    1    Characteristics  Crude OR (95% CI)  P-value  Adjusted OR (95% CI)  P-value  Smoking status              Smoker/ex-smoker  1.39 (1.09–1.77)  0.01  1.32 (1.04–1.68)  0.02      Non smoker  1    1    Age group              65–74 years  1    1        75–84  0.85 (0.57–1.27)  0.42  0.87 (0.57–1.32)  0.76      ≥85 years  1.13 (0.63–2.00)  0.69  1.28 (0.71–2.32)  0.42  Marital status              Married/cohabiting  1    1        Single  0.57 (0.39–0.83)  0.004  0.54 (0.36–0.79)  0.001      Widowed  0.76 (0.61–0.95)  0.02  0.73 (0.58–0.92)  0.007      Separated/divorced  1.17 (0.68–2.00)  0.57  1.13 (0.66–1.95)  0.66  Barthel index              >60  1.25 (0.97–1.60)  0.08  1.31 (1.02–1.70)  0.03      0–60  1    1    Any medical conditions              High risk  1.23 (1.01–1.50)  0.04  1.27 (1.04–1.56)  0.02      Non high risk  1    1    Influenza vaccination              Yes  0.73 (0.61–0.87)  <0.001  0.70 (0.58–0.83)  <0.001      No  1    1    The influenza vaccine was effective in preventing hospitalization both in current smokers/ex-smokers and non-smokers but was slightly lower in smokers/ex-smokers in whom it was not statistically significant due to the lower statistical power. Influenza vaccine effectiveness in current smokers/ex-smokers was 21% (95% CI: -2 to 39) and 39% in non-smokers (95% CI: 22–52) (Table 4). Table 4 Effectiveness of influenza vaccine in avoiding influenza hospitalization in patients aged ≥ 65 years with laboratory-confirmed influenza in regression models according to smoking status   Cases vaccinated/N (%)  Controls vaccinated/N (%)  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Smoking status              Smoker/ex-smokera  175/345 (50.7%)  420/769 (54.6%)  0.85 (0.66–1.10)  0.11  0.79 (0.61–1.02)  0.08  Non-smoker a  184/383 (48.0%)  633/1057 (59.9%)  0.62 (0.49–0.78)  <0.001  0.61 (0.48–0.78)  <0.001    Cases vaccinated/N (%)  Controls vaccinated/N (%)  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Smoking status              Smoker/ex-smokera  175/345 (50.7%)  420/769 (54.6%)  0.85 (0.66–1.10)  0.11  0.79 (0.61–1.02)  0.08  Non-smoker a  184/383 (48.0%)  633/1057 (59.9%)  0.62 (0.49–0.78)  <0.001  0.61 (0.48–0.78)  <0.001  OR, odds ratio; CI, confidence interval. a Adjusted OR for: age group, marital status, high alcohol consumption, Barthel index, risk medical conditions. Discussion The results of this study of cases aged ≥ 65 years hospitalized due to influenza and their corresponding controls show that the risk of influenza hospitalization was 30% higher in patients with a history of smoking (smokers and ex-smokers). After controlling for potential confounders and influenza vaccination, smoking was responsible for 24.2% of hospitalizations due to influenza in patients with a history of smoking. The results hold true for different age groups, with variations attributable to the low power of the analysis, and in females, who had a much higher risk than men, probably due to different patterns of susceptibility to tobacco. In addition, the influenza vaccine was effective in preventing hospitalization but was slightly less effective in smokers/ex-smokers than in non-smokers. The estimated risk of influenza hospitalization in patients with a history of smoking (aOR = 1.31) may be attributed to the effects of tobacco in ex-smokers aged ≥ 65 years. Similarly, we estimated in another study11 that the risk of hospitalization was slightly higher (aOR = 1.73) in ex-smokers aged ≥18 years although lower than in smokers (aOR = 2.18). Likewise, Ward et al.17 found that the risk of hospitalization remains very high in ex-smokers aged ≥16 years (aOR = 2.18). All these studies reported that the risk of hospitalization was greater, although less so, in ex-smokers, suggesting that the lesions caused by smoking remain over time, although their effects lessen. The risk of the history of smoking on influenza hospitalization remained in different age groups, with variations due to the low power of the analysis in some cases. There was an increased risk in patients with a history of smoking aged ≥ 85 years. Likewise, other studies suggest the increased risk in ex-smokers may be due to the cumulative effect of smoking over time.11,18 The risk of influenza hospitalization in patients aged ≥65 years with a history of smoking was greater in females than in males. The study by Kark et al.19 showed a higher risk ratio in female soldiers who smoked (RR = 1.44) than in those who did not, while Ward et al.17 reported a higher risk of influenza hospitalization in female former smokers of childbearing age (OR = 2.8). In contrast, other studies found a higher risk in male smokers than in female smokers and ex-smokers.11,17 As we only studied the history of smoking in patients aged ≥ 65 years, a possible survival effect in males and smokers cannot be ruled out, as women and never-smokers tend to live longer.16 Influenza vaccine effectiveness was moderate (21% in smokers and 39% in non-smokers), and was similar to that found in other observational studies in patients aged ≥ 65 years.20 Furthermore, influenza vaccination is strong recommended by the main public health agencies.21,22 The prevalence of smoking in controls was higher in non-influenza vaccinated patients than in vaccinated ones and suggests, similar to other studies, that a history of smoking may be negatively associated with influenza vaccination.23 Vander et al. found that, in the Behavioral Risk Factor Surveillance System of US adults, daily smokers were less likely to receive influenza vaccination despite their increased risk for respiratory disease.24 Our results are consistent with studies in animal models which found that smoking damages the immune system of the airways, causing a reduction in interferon gamma (IFN γ) and CD4 lymphocytes, thus enabling not only infection but also the severity of influenza.4,13,25 A cohort study26 in volunteer smokers, ex-smokers, second-hand smokers and non-smokers who were inoculated with an attenuated influenza virus in the nasal mucosa found not only suppression of the response to the virus but also a higher viral load in people exposed to smoking. It also found greater disease severity and persistence of the effect of smoking in ex-smokers. This study has some limitations. Smoking consumption was collected through interviews and the history of smoking was self-reported by patients. However, as all patients, cases and controls were hospitalized and as a structured questionnaire was used, potential observer bias was minimized. We also matched cases and controls for the date of hospitalization ± 10 days, to avoid recall bias or other errors associated with the moment patients contacted the health system. Some risk factors were related to age. We matched cases and control by age ± 3 years to control for the effect of age and to obtain a sufficient number of controls for logistic reasons. In cases and controls, the prevalence of smoking decreased with age and was much higher in males than in females. Therefore, the risk in some subgroups (males and younger adults) may have been diluted by the possible confounding effect of sex and age.16 For this reason, we also estimated the risks using separate regression models according to gender and age group. The outcome measure used in this study was hospitalization due to influenza, and smoking is also associated with an increased risk of other factors that influence hospitalization, including the marital status, high alcohol consumption, the Barthel index and chronic diseases including COPD, diabetes, congestive heart disease and renal failure.15,27 However, all these variables were entered in the final regression models and their effects controlled for, but residual confounding cannot be ruled out. The results of this study have implications for public health. The fraction of the risk of influenza hospitalization attributable to smoking was 24.2% in smokers and ex-smokers aged ≥65 years, slightly lower than the 40.6% found by Kark et al.,9 and suggests that patients with a history of smoking should be informed about their risk of hospitalization due to influenza. Likewise, studies have shown lower rates of influenza vaccination in smokers23,28 which could add to the negative effect of smoking. The effectiveness of influenza vaccination in our study was slightly lower in smokers than in non-smokers. Horvath et al. found that cytotoxic NK cell activity and IFNγ levels were suppressed in smokers following live attenuated influenza vaccination.29 However, Woolpert et al. studied 28 929 vaccination events during two influenza seasons, including 22 734 (79%) live attenuated vaccinations and 6195 (21%) trivalent inactivated influenza vaccinations, and found that, in the final adjusted model, the relative effectiveness of the two vaccine types did not differ by smoking status (P = 0.10).30 Other studies have shown a high effectiveness of influenza vaccination in vaccinated smokers compared with non-vaccinated smokers.23 Therefore, smoking should be an indication for vaccination for current smokers and ex-smokers, as suggested by the Centers for Disease Control and Prevention for the 23-valent pneumococcal polysaccharide vaccine.31 In conclusion, a history of smoking may increase the risk of hospitalization in smokers and ex-smokers. Preventing smoking could reduce hospitalizations due to influenza. Smokers and ex-smokers should be informed of the risk of hospitalization due to influenza infection, and encouraged to stop smoking. Smokers should be considered an at-risk group to be aggressively targeted for routine influenza vaccination. Supplementary data Supplementary data are available at EURPUB online. Acknowledgements The other members of the CIBERESP Cases and Controls in Pandemic Influenza Working Group are: Andalusia: J. Díaz-Borrego (Servicio Andaluz de Salud), A. Morillo (Hospital Universitario Virgen del Rocío), M.J. Pérez-Lozano (Hospital Universitario Virgen de Valme), J. Gutiérrez (Hospital Universitario Puerta del Mar), M. Pérez-Ruiz, M.A. Fernández-Sierra (Hospital Universitario San Cecilio y Virgen de las Nieves), M.A. Fernández-Sierra (Complejo Hospitalario Universitario de Granada); Castile and Leon: S. Tamames (Dir. General de Salud Pública, Investigación, Desarrollo e Innovación, Junta de Castilla y León), S. Rojo-Rello (Hospital Clínico Universitario de Valladolid), R. Ortiz de Lejarazu (Universidad de Valladolid), M.I. Fernández-Natal (Complejo Asistencial Universitario de León), T. Fernández-Villa (GIIGAS-Grupo de Investigación en Interacción Gen-Ambiente y Salud, Universidad de León), A. Pueyo (Hospital Universitario de Burgos); Catalonia: A. Vilella (Hospital Clínic), M. Campins, A. Antón (Hospital Universitari Vall d’Hebron; Universitat Autónoma de Barcelona), G. Navarro (Corporació Sanitària i Universitaria Parc Taulí), M. Riera (Hospital Universitari MútuaTerrassa), E. Espejo (Hospital de Terrassa), M.D. Mas, R. Pérez (ALTHAIA, Xarxa Hospitalaria de Manresa), J.A. Cayla, C. Rius (Agència de Salut Pública de Barcelona; CIBERESP), N. Torner (Agència de Salut Pública de Catalunya; Universitat de Barcelona; CIBERESP), C. Izquierdo, R. Torra (Agència de Salut Pública de Catalunya), L. Force (Hospital de Mataró), I. Crespo (Universitat de Barcelona; CIBERESP); Madrid: M.F. Domínguez-Berjon, M.A. Gutiérrez, S. Jiménez, E. Gil, F. Martín, R. Génova-Maleras (Consejería de Sanidad), M.C. Prados, F. Enzzine de Blas, M.A. Salvador (Hospital Universitario la Paz), J.C Galán, E. Navas, L. Rodríguez (Hospital Ramón y Cajal), C.J. Álvarez, E. Banderas, S. Fernandez (Hospital Universitario 12 de Octubre); Navarra: J. Chamorro (Complejo Hospitalario de Navarra), I. Casado, J. Díaz (Instituto de Salud Pública de Navarra); The Basque Country: M.J. López de Goicoechea (Hospital de Galdakao); Valencia Community: F. Sanz (Consorci Hospital General Universitari de Valencia). Funding This study was funded by the National Plan of I + D+I 2008–2011 and ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Project PI12/02079) and cofunded by Fondo Europeo de Desarrollo Regional (FEDER. Unión Europea. Una manera de hacer Europa), and the Catalan Agency for the Management of Grants for University Research (AGAUR Grant number 2014/SGR 1403). This study was supported by the Ministry of Science and Innovation, Instituto de Salud Carlos III, Project PI12/02079. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflicts of interest: No author has any commercial or other association that might pose a conflict of interest. Key points Smoking was associated with an increased risk of influenza hospitalization due to influenza in the elderly. Smoking reduces influenza vaccine effectiveness in the elderly. Smoking prevention could reduce hospitalizations due to influenza. References 1 Horby P, Mai LQ, Fox A, et al.   The epidemiology of interpandemic and pandemic influenza in Vietnam, 2007–2010 The Ha Nam Household Cohort Study I. Am J Epidemiol  2012; 175: 1062– 74. Google Scholar CrossRef Search ADS PubMed  2 INE. Encuesta Nacional de Salud, 2014. Determinantes de salud (consumo de tabaco, exposición pasiva al humo de tabaco, alcohol, problemas medioambientales en la vivienda) (updated on 20/5/2015). Madrid; 2015. http://www.ine.es/ss/Satellite?L=es_ES&c=INESeccion_C&cid=1259926698156&p=1254735110672&pagename=ProductosYServicios%2FPYSLayout. 3 van Zyl Smit RN, Pai M, Yew WW, et al.   Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD. Eur Respir J  2010; 35: 27– 33. Google Scholar CrossRef Search ADS PubMed  4 Feng Y, Kong Y, Barnes PF, et al.   Exposure to cigarette smoke inhibits the pulmonary T-cell response to influenza virus and Mycobacterium tuberculosis. Infect Immun  2011; 79: 229. Google Scholar CrossRef Search ADS PubMed  5 Murin S, Bilello KS. Respiratory tract infections: another reason not to smoke. Cleve Clin J Med  2005; 72: 916– 20. Google Scholar CrossRef Search ADS PubMed  6 Almirall J, Bolibar I, Serra-Prat M, et al.   New evidence of risk factors for community-acquired pneumonia: a population-based study. Eur Respir J  2008; 31: 1274– 84. Google Scholar CrossRef Search ADS PubMed  7 Epstein MA, Reynaldo S, El-Amin AN. Is smoking a risk factor for influenza hospitalization and death? J Infect Dis  2010; 201: 794– 5. Google Scholar CrossRef Search ADS PubMed  8 Finklea JF, Hasselblad V, Riggan WB, et al.   Cigarette smoking and hemagglutination inhibition response to influenza after natural disease and immunization. Am Rev Respir Dis  1971; 104: 368– 76. Google Scholar CrossRef Search ADS PubMed  9 Kark JD, Lebiush M, Rannon L. Cigarette smoking as a risk factor for epidemic A(H1N1) influenza in young men. N Engl J Med  1982; 307: 1042– 6. Google Scholar CrossRef Search ADS PubMed  10 Wong CM, Chan WM, Yang L, et al.   Effect of lifestyle factors on risk of mortality associated with influenza in elderly people. Hong Kong Med J  2014; 20: 16– 9. Google Scholar PubMed  11 Godoy P, Castilla J, Mayoral JM, et al.   Smoking may increase the risk of hospitalization due to influenza. Eur J Public Health  2016; 45: 882– 7. Google Scholar CrossRef Search ADS   12 Kotani N, Kushikata T, Hashimoto H, et al.   Recovery of intraoperative microbiocidal and inflammatory functions of alveolar immune cells after a tobacco smoke-free period. Anesthesiology  2001; 94: 999– 1006. Google Scholar CrossRef Search ADS PubMed  13 Gualano RC, Hansen MJ, Vlahos R, et al.   Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice. Respir Res BioMed Central  2008; 9: 53. 14 Huttunen R, Heikkinen T, Syrjanen J. Smoking and the outcome of infection. J Intern Med  2011; 269: 258– 69. Google Scholar CrossRef Search ADS PubMed  15 Lin HH, Ezzati M, Murray M. Tobacco smoke, indoor air pollution and tuberculosis: a systematic review and meta-analysis. PLoS Med  2007; 4: e20. Google Scholar CrossRef Search ADS PubMed  16 Wong CM, Yang L, Chan KP, et al.   Cigarette smoking as a risk factor for influenza-associated mortality: evidence from an elderly cohort. Influenza Other Respir Viruses  2013; 7: 531– 9. Google Scholar CrossRef Search ADS PubMed  17 Ward KA, Spokes PJ, McAnulty JM. Case–control study of risk factors for hospitalization caused by pandemic (H1N1) 2009. Emerg Infect Dis  2011; 17: 1409– 16. Google Scholar PubMed  18 Nuorti JP, Butler JC, Farley MM, et al.   Cigarette smoking and invasive pneumococcal disease. Active Bacterial Core Surveillance Team. N Engl J Med  2000; 342: 681– 9. Google Scholar CrossRef Search ADS PubMed  19 Kark JD, Lebiush M. Smoking and epidemic influenza-like illness in female military recruits: a brief survey. Am J Public Health  1981; 71: 530– 2. Google Scholar CrossRef Search ADS PubMed  20 Jefferson T, Ferroni E, Thorning S, et al.   Vaccines for preventing influenza in the elderly. Cochrane Database Syst  2010; 2: 2– 4. 21 WHO. Vaccines against influenza WHO position paper – November 2012. Wkly Epidemiol Rec  2012; 87: 461– 76. PubMed  22 Mereckiene J, Cotter S, Weber JT, et al.   Influenza A(H1N1)pdm09 vaccination policies and coverage in Europe. Eurosurveillance  2012; 17: 1– 10. Google Scholar CrossRef Search ADS   23 Nicholson KG, Kent J, Hammersley V. Influenza A among community-dwelling elderly persons in Leicestershire during winter 1993-4; cigarette smoking as a risk factor and the efficacy of influenza vaccination. Epidemiol Infect  1999; 123: 103. Google Scholar CrossRef Search ADS PubMed  24 Vander Weg MW, Bryant Howren M, Cai X. Use of routine clinical preventive services among daily smokers, non-daily smokers, former smokers, and never-smokers. Nicotine Tobacco Res  2012; 14: 123– 30. Google Scholar CrossRef Search ADS   25 Horvath KM, Brighton LE, Zhang W, et al.   Epithelial cells from smokers modify dendritic cell responses in the context of influenza infection. Am J Respir Cell Mol Biol  2011; 45: 237– 45. Google Scholar CrossRef Search ADS PubMed  26 Noah TL, Zhou H, Monaco J, et al.   Tobacco smoke exposure and altered nasal responses to live attenuated influenza virus. Environ Health Perspect  2011; 119: 78. Google Scholar CrossRef Search ADS PubMed  27 van Zyl-Smit RN, Brunet L, Pai M, Yew WW. The convergence of the global smoking, COPD, Tuberculosis, HIV, and respiratory infection epidemics. Infect Dis Clin North Am  2010; 24: 693. Google Scholar CrossRef Search ADS PubMed  28 Ohmit SE, Furumoto-Dawson A, Monto AS, Fasano N. Influenza vaccine use among an elderly population in a community intervention. Am J Prev Med  1995; 11: 271– 6. Google Scholar PubMed  29 Horvath KM, Herbst M, Zhou H, et al.   Nasal lavage natural killer cell function is suppressed in smokers after live attenuated influenza virus. Respir Res  2011; 12: 102. Google Scholar CrossRef Search ADS PubMed  30 Woolpert T, Phillips CJ, Sevick C, et al.   Health-related behaviors and effectiveness of trivalent inactivated versus live attenuated influenza vaccine in preventing influenza-like illness among young adults. PLoS One  2014; 9: e102154. Google Scholar CrossRef Search ADS PubMed  31 Nuorti JP, Whitney CG. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep  2010; 59: 1102– 6. Google Scholar PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. 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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.
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1101-1262
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1464-360X
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10.1093/eurpub/ckx130
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Abstract

Abstract Background Through its effects on the immune system, smoking may facilitate influenza virus infection, its severity and its most frequent complications. The objective was to investigate the smoking history as a risk factor for influenza hospitalization and influenza vaccine effectiveness in elderly smokers/ex-smokers and non-smokers. Methods We carried out a multicenter case–control study in the 2013–2014 and 2014–2015 influenza seasons. Cases aged ≥65 years and age-, sex-matched controls were selected from 20 Spanish hospitals. We collected epidemiological variables, comorbidities, vaccination history and the smoking history. The risk of hospitalization due to smoking (current smokers and ex-smokers) was determined using the adjusted odds ratio (aOR) with conditional logistic regression models. Vaccine effectiveness (VE) was calculated using the formula: VE = (1 – aOR) × 100. Results We studied 728 cases and 1826 controls. Cases had a higher frequency of smoking (47.4% vs 42.1%). Smoking was associated with an increased risk of influenza hospitalization (aOR = 1.32, 95% CI: 1.04–1.68). Influenza vaccine effectiveness in preventing hospitalization was 21% (95% CI: -2 to 39) in current/ex-smokers and 39% in non-smokers (95% CI: 22–52). Conclusions A history of smoking may increase the risk of hospitalization in smokers and ex-smokers. Preventing smoking could reduce hospitalizations due to influenza. Smokers and ex-smokers should be informed of the risk of hospitalization due to influenza infection, and encouraged to stop smoking. Smokers should be considered an at-risk group to be aggressively targeted for routine influenza vaccination. Introduction Influenza affects a large percentage of the population each year, with estimates as high as 15%.1 The smoking prevalence of 30.5% in men and 20.5% in woman found in the Spanish population according to the latest National Health Survey remains very high,2 but is lower in the elderly (16.2% in men and 4.6% in woman aged 65–74 years). Smoking favors the frequency and severity of several respiratory diseases.3 Tobacco smoke causes the deposition of particles in the airways that damage the protection mechanisms of the respiratory system at different levels, alters the function of the ciliary mucus and the clearance of inhaled substances, enables the adherence of bacteria to airway epithelial cells, increases alveolar permeability and decreases cellular and humoral immunity.4,5 Through these effects on the immune system, smoking may facilitate influenza virus infection, its severity, and its most frequent complications, such as bacterial pneumonia.6,7 Studies have estimated that smokers have more than twice the risk of clinical disease8,9 compared with non-smokers and also present more severe forms.10 Some authors suggest that these effects are dependent on the chronicity of smoking and may persist, although to a lesser extent, after stopping smoking.11–13 The presence of concomitant diseases strongly associated with smoking, such as chronic obstructive pulmonary disease (COPD) and congestive heart disease, make it difficult to assess the role of smoking in increasing the severity of influenza.14,15 The role of smoking in influenza in the elderly may be more difficult to assess due to the lower prevalence of smokers and the higher prevalence of ex-smokers and because some smokers die before the age of 65 years due to tobacco-related causes.16 Thus, there is a need to determine the effect of smoking as a risk factor for influenza hospitalization in the elderly. The aim of this study was to estimate the smoking history as a risk factor for influenza hospitalization and influenza vaccine effectiveness in smokers/ex-smokers and non-smokers in the 2013–2014 and 2014–2015 influenza seasons in Spain in people aged ≥65 years. Methods Study design We designed a multicenter, case–control study in 20 Spanish hospitals from seven Spanish regions (Andalusia, the Basque Country, Castile and Leon, Catalonia, Madrid, Navarre and Valencia Community). All were public reference hospitals located in the main cities of each community and all provided free-at-the-point-of-delivery healthcare under the auspices of the Spanish National Health Service. Cases hospitalized due to influenza in the participating hospitals in the 2013–2014 and 2014–2015 influenza seasons and corresponding inpatient controls were recruited. Selection of cases and controls Patients aged ≥65 years hospitalized for at least 24 h with laboratory-confirmed influenza virus infection [reverse-transcription polymerase chain reaction (RT-PCR), culture or immunofluorescence] were selected. Patients with nosocomial infection, defined as influenza virus infection appearing ≥ 48 h after admission for other reasons, were excluded. Three matched controls were selected for each case from patients aged ≥65 years with unplanned hospital admission due to causes other than influenza or acute respiratory disease. Controls were matched with each case according to age (±3 years), sex and date of hospitalization (±10 days). Controls were selected from patients admitted to the general surgery, internal medicine service, ophthalmology, otorhinolaryngology, dermatology, or traumatology services. Patients referred from nursing homes and those who did not provide written informed consent were excluded. Data collection Hospitalized cases and controls were interviewed by specifically-trained health professionals using the same structured questionnaire at a similar time after hospitalization and their medical records were reviewed. The following demographic variables and pre-existing medical conditions were recorded: age, sex, marital status, educational level, smoking and alcohol intake, the Barthel index as a measurement of limitations in activity (ranging from 0—complete dependence to 100—complete independence), COPD, chronic respiratory failure, history of pneumonia during the last two years, other lung diseases, neoplasia, transplantation, diabetes, renal failure, congestive heart disease, disabling neurological disease, obesity [body mass index (BMI) ≥ 30] and chronic liver disease. Definition We defined the variable ‘Any risk medical condition’ as: Yes (≥1: COPD, congestive heart disease, renal failure, diabetes, chronic liver disease) or No (no risk medical conditions). High alcohol consumption as: Yes (>40 g/day for men and >24 g/day for women) or No. Smoking was defined as habitual smoker (any smoking in the last 6 months), ex-smoker (former smoker who gave up and had not smoked in the last 6 months) and never smoker. As the prevalence of smokers was very low, we combined smoker and ex-smoker in the same category for the analysis. Information on the seasonal influenza vaccine status and pneumococcal vaccination status was obtained from medical records or vaccination cards. Cases and controls were considered vaccinated with the seasonal influenza vaccine if they had received a dose of the trivalent inactivated vaccine at least 14 days before the onset of symptoms of the case. Statistical analysis A bivariate comparison was made between cases and controls for demographic variables, smoking, alcohol intake, Barthel index, influenza vaccine and any medical conditions using the McNemar test for categorical variables. Unadjusted matched odds ratios (OR) were estimated using the McNemar test. Multivariate analysis using conditional logistic regression was made to estimate the adjusted OR (aOR) for smoking status (smokers and ex-smokers). Covariates were introduced into the model using a backward stepwise procedure, with a cut-off point of P < 0.2. In the different regression models, the aOR for smoking for all cases and controls considered together and by sex and age-group (65–74; 75–84; and ≥85 years) were calculated to evaluate possible differences and rule out selection bias. The analysis according to sex or age group was adjusted using conditional logistic regression. The effect of the vaccine was evaluated according to the smoking categories (smokers/ex-smokers and nonsmokers) using unconditional logistic regression with backward selection of variables, with a cut-off point of P < 0.2. Vaccine effectiveness (VE) was calculated using the formula: VE = (1 – aOR) × 100. The fraction of influenza hospitalization attributable to smoking in the exposed population was calculated by estimating the attributable risk in the exposed population: (ARe) = [(aOR–1)/(aOR–1) + 1] × 100. The analysis was performed using the SPSS v.23 statistical package and the R v3.3.0 statistical software (http://cran.r-project.org). Ethical considerations All data collected were treated as confidential, in strict observance of legislation on observational studies. The study was approved by the Ethics Committees of the participating hospitals. Written informed consent was obtained from all patients included in the study. Results We studied 728 cases with RT-PCR-confirmed influenza (443 cases from season 2013–2014 and 295 from season 2014–2015) and 1826 controls. Cases and controls had a similar frequency of females (47.1% vs 48.4%), and patients in each age group (P = 0.29) (Table 1). However, compared with controls, cases had a different distribution of the marital status (P = 0.02) and the Barthel index (P = 0.08), a lower prevalence of influenza vaccination (49.3% vs 57.7%; P < 0.001) and a higher frequency of smoking (47.4% vs 42.1%; P = 0.01) (Table 1). The proportion of ex-smokers and current smokers was 39.6% and 7.8% in cases vs 35.0% and 7.1% in controls. Table 1 Distribution of cases and controls according to demographic variables, medical conditions and vaccination history Characteristics  Cases  Controls  P-value  (N = 728)  (N = 1826)  Smoking status            Smoker  57 (7.8%)  130 (7.1%)        Ex-smoker  288 (39.6%)  639 (35.0%)        Smoker/ex-smoker  345 (47.4%)  769 (42.1%)        Non smoker  383 (52.6%)  1057 (57.9%)  0.01  Age group            65–74 years  248 (34.1%)  614 (33.6%)        75–84 years  340 (46.7%)  883 (48.4%)        ≥85 years  140 (19.2%)  329 (18.0%)  0.29  Sex            Female  343 (47.1%)  884 (48.4)        Male  385 (52.9%)  942 (51.6%)  1.00  Marital status            Married/cohabiting  450 (61.9%)  1020 (56.0%)        Single  39 (5.4%)  145 (8.0%)        Widowed  217 (29.8%)  615 (33.8%)        Separated/divorced  21 (2.9%)  42 (2.3%)  0.02  Barthel index            0–60  123 (16.9%)  336 (20.1%)  0.08      >60  605 (83.1%)  1458 (70.9%)    High alcohol consumption            Yes  16 (2.2%)  53 (2.9%)        No  712 (97.8%)  1772 (97.1%)  0.38  Risk medical conditions            Yes  507 (69.6%)  1217 (66.6%)        No  221 (30.4%)  609 (33.4%)  0.04  Influenza vaccine            Yes  359 (49.3%)  1053 (57.7%)  <0.001      No  369 (50.7%)  773 (42.3%)    Pneumococcal vaccine            Yes  372 (51.1%)  836 (45.8%)  0.06      No  356 (48.9%)  990 (54.2%)    Characteristics  Cases  Controls  P-value  (N = 728)  (N = 1826)  Smoking status            Smoker  57 (7.8%)  130 (7.1%)        Ex-smoker  288 (39.6%)  639 (35.0%)        Smoker/ex-smoker  345 (47.4%)  769 (42.1%)        Non smoker  383 (52.6%)  1057 (57.9%)  0.01  Age group            65–74 years  248 (34.1%)  614 (33.6%)        75–84 years  340 (46.7%)  883 (48.4%)        ≥85 years  140 (19.2%)  329 (18.0%)  0.29  Sex            Female  343 (47.1%)  884 (48.4)        Male  385 (52.9%)  942 (51.6%)  1.00  Marital status            Married/cohabiting  450 (61.9%)  1020 (56.0%)        Single  39 (5.4%)  145 (8.0%)        Widowed  217 (29.8%)  615 (33.8%)        Separated/divorced  21 (2.9%)  42 (2.3%)  0.02  Barthel index            0–60  123 (16.9%)  336 (20.1%)  0.08      >60  605 (83.1%)  1458 (70.9%)    High alcohol consumption            Yes  16 (2.2%)  53 (2.9%)        No  712 (97.8%)  1772 (97.1%)  0.38  Risk medical conditions            Yes  507 (69.6%)  1217 (66.6%)        No  221 (30.4%)  609 (33.4%)  0.04  Influenza vaccine            Yes  359 (49.3%)  1053 (57.7%)  <0.001      No  369 (50.7%)  773 (42.3%)    Pneumococcal vaccine            Yes  372 (51.1%)  836 (45.8%)  0.06      No  356 (48.9%)  990 (54.2%)    The prevalence of smoking among cases was 58.9% in the 65–74 years age group, 45.6% in the 75–84 years age group and 31.4% in the ≥85 years age group; 75.3% in males vs 16.0% in females (P < 0.001); 66.7% in separated/divorced people, 59.0% in single people, 54.0% in married/cohabiting subjects and 29.5% in widowed persons; 51.2% in patients with a higher Barthel index vs 28.5% in those without (P < 0.001); 81.3% in patients with high alcohol consumption vs 46.6% in those without (P < 0.001); and 52.7% in persons with any risk medical condition vs 35.3% in those without (P < 0.001) (Table 2). Controls had a lower prevalence of smoking than cases although the patterns and differences within groups were similar (Table 2). In addition, the prevalence of smoking in non-vaccinated controls was 45.1% compared with 39.9% in vaccinated controls (P = 0.02) (Table 2). Table 2 Distribution of smoking status in cases and controls according to demographic variables, medical conditions and vaccination history   Smoking/total, n/N (%)  Characteristics  Cases  P-value  Controls  P-value  Total  345/728 (47%)    769/1826 (42%)    Age group              65–74 years  146 (58.9%)    329 (53.6%)        75–84 years  155 (45.6%)    367 (41.6%)        ≥85 years  44 (31.4%)  <0.001  73 (22.2%)  <0.001  Sex              Female  55 (16.0%)    82 (9.3)        Male  290 (75.3%)  <0.001  687 (72.9%)  <0.001  Marital status              Married/cohabiting  243 (54.0%)    521 (51.0%)        Single  23 (59.0%)    66 (45.5%)        Widowed  64 (29.5%)    151 (24.6%)        Separated/divorced  14 (66.7%)  <0.001  31 (73.8%)  <0.001  Barthel index              0–60  35 (28.5%)    128 (35.0%)        >60  310 (51.2%)  <0.001  641 (43.9%)  <0.001  High alcohol consumption              No  332 (46.6%)    721 (40.7%)        Yes  13 (81.3%)  <0.001  48 (90.6%)  <0.001  Risk medical conditions              Yes  267 (52.7%)    579 (47.6%)        No  78 (35.3%)  <0.001  190 (31.2%)  <0.001  Influenza vaccine              Yes  175 (48.7%)    420 (39.9%)        No  170 (46.1%)  0.47  349 (45.1%)  0.02  Pneumococcal vaccine              Yes  180 (48.4%)    328 (39.2%)        No  165 (46.3%)  0.58  441 (44.5%)  0.02    Smoking/total, n/N (%)  Characteristics  Cases  P-value  Controls  P-value  Total  345/728 (47%)    769/1826 (42%)    Age group              65–74 years  146 (58.9%)    329 (53.6%)        75–84 years  155 (45.6%)    367 (41.6%)        ≥85 years  44 (31.4%)  <0.001  73 (22.2%)  <0.001  Sex              Female  55 (16.0%)    82 (9.3)        Male  290 (75.3%)  <0.001  687 (72.9%)  <0.001  Marital status              Married/cohabiting  243 (54.0%)    521 (51.0%)        Single  23 (59.0%)    66 (45.5%)        Widowed  64 (29.5%)    151 (24.6%)        Separated/divorced  14 (66.7%)  <0.001  31 (73.8%)  <0.001  Barthel index              0–60  35 (28.5%)    128 (35.0%)        >60  310 (51.2%)  <0.001  641 (43.9%)  <0.001  High alcohol consumption              No  332 (46.6%)    721 (40.7%)        Yes  13 (81.3%)  <0.001  48 (90.6%)  <0.001  Risk medical conditions              Yes  267 (52.7%)    579 (47.6%)        No  78 (35.3%)  <0.001  190 (31.2%)  <0.001  Influenza vaccine              Yes  175 (48.7%)    420 (39.9%)        No  170 (46.1%)  0.47  349 (45.1%)  0.02  Pneumococcal vaccine              Yes  180 (48.4%)    328 (39.2%)        No  165 (46.3%)  0.58  441 (44.5%)  0.02  In the multivariate analysis, smoking (aOR = 1.32, 95% CI: 1.04–1.68) was significantly associated with the risk of influenza hospitalization (P = 0.02) (Table 3). In the logistic regression models according to age groups, the aOR between smoking and influenza hospitalization was > 1 in all age groups, but was only statistically significant in the ≥85 years age group (aOR = 2.27, 95% CI: 1.16–4.44) due to the low power of the estimates. Analysis by sex showed that the aOR for influenza hospitalization were all > 1, but were higher in females (aOR = 1.95, 95% CI: 1.28–2.97) than in males (aOR = 1.14, 95% CI: 0.85–1.52) (Supplementary Table). The fraction of the risk of influenza hospitalization attributable to smoking was 24.2% (95% CI: 3.84% to -410.5%) in current smokers/ex-smokers. Table 3 Smoking status (smoker and ex-smoker) as a risk factor for hospitalization in patients aged ≥ 65 years with laboratory-confirmed influenza in the regression model Characteristics  Crude OR (95% CI)  P-value  Adjusted OR (95% CI)  P-value  Smoking status              Smoker/ex-smoker  1.39 (1.09–1.77)  0.01  1.32 (1.04–1.68)  0.02      Non smoker  1    1    Age group              65–74 years  1    1        75–84  0.85 (0.57–1.27)  0.42  0.87 (0.57–1.32)  0.76      ≥85 years  1.13 (0.63–2.00)  0.69  1.28 (0.71–2.32)  0.42  Marital status              Married/cohabiting  1    1        Single  0.57 (0.39–0.83)  0.004  0.54 (0.36–0.79)  0.001      Widowed  0.76 (0.61–0.95)  0.02  0.73 (0.58–0.92)  0.007      Separated/divorced  1.17 (0.68–2.00)  0.57  1.13 (0.66–1.95)  0.66  Barthel index              >60  1.25 (0.97–1.60)  0.08  1.31 (1.02–1.70)  0.03      0–60  1    1    Any medical conditions              High risk  1.23 (1.01–1.50)  0.04  1.27 (1.04–1.56)  0.02      Non high risk  1    1    Influenza vaccination              Yes  0.73 (0.61–0.87)  <0.001  0.70 (0.58–0.83)  <0.001      No  1    1    Characteristics  Crude OR (95% CI)  P-value  Adjusted OR (95% CI)  P-value  Smoking status              Smoker/ex-smoker  1.39 (1.09–1.77)  0.01  1.32 (1.04–1.68)  0.02      Non smoker  1    1    Age group              65–74 years  1    1        75–84  0.85 (0.57–1.27)  0.42  0.87 (0.57–1.32)  0.76      ≥85 years  1.13 (0.63–2.00)  0.69  1.28 (0.71–2.32)  0.42  Marital status              Married/cohabiting  1    1        Single  0.57 (0.39–0.83)  0.004  0.54 (0.36–0.79)  0.001      Widowed  0.76 (0.61–0.95)  0.02  0.73 (0.58–0.92)  0.007      Separated/divorced  1.17 (0.68–2.00)  0.57  1.13 (0.66–1.95)  0.66  Barthel index              >60  1.25 (0.97–1.60)  0.08  1.31 (1.02–1.70)  0.03      0–60  1    1    Any medical conditions              High risk  1.23 (1.01–1.50)  0.04  1.27 (1.04–1.56)  0.02      Non high risk  1    1    Influenza vaccination              Yes  0.73 (0.61–0.87)  <0.001  0.70 (0.58–0.83)  <0.001      No  1    1    The influenza vaccine was effective in preventing hospitalization both in current smokers/ex-smokers and non-smokers but was slightly lower in smokers/ex-smokers in whom it was not statistically significant due to the lower statistical power. Influenza vaccine effectiveness in current smokers/ex-smokers was 21% (95% CI: -2 to 39) and 39% in non-smokers (95% CI: 22–52) (Table 4). Table 4 Effectiveness of influenza vaccine in avoiding influenza hospitalization in patients aged ≥ 65 years with laboratory-confirmed influenza in regression models according to smoking status   Cases vaccinated/N (%)  Controls vaccinated/N (%)  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Smoking status              Smoker/ex-smokera  175/345 (50.7%)  420/769 (54.6%)  0.85 (0.66–1.10)  0.11  0.79 (0.61–1.02)  0.08  Non-smoker a  184/383 (48.0%)  633/1057 (59.9%)  0.62 (0.49–0.78)  <0.001  0.61 (0.48–0.78)  <0.001    Cases vaccinated/N (%)  Controls vaccinated/N (%)  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Smoking status              Smoker/ex-smokera  175/345 (50.7%)  420/769 (54.6%)  0.85 (0.66–1.10)  0.11  0.79 (0.61–1.02)  0.08  Non-smoker a  184/383 (48.0%)  633/1057 (59.9%)  0.62 (0.49–0.78)  <0.001  0.61 (0.48–0.78)  <0.001  OR, odds ratio; CI, confidence interval. a Adjusted OR for: age group, marital status, high alcohol consumption, Barthel index, risk medical conditions. Discussion The results of this study of cases aged ≥ 65 years hospitalized due to influenza and their corresponding controls show that the risk of influenza hospitalization was 30% higher in patients with a history of smoking (smokers and ex-smokers). After controlling for potential confounders and influenza vaccination, smoking was responsible for 24.2% of hospitalizations due to influenza in patients with a history of smoking. The results hold true for different age groups, with variations attributable to the low power of the analysis, and in females, who had a much higher risk than men, probably due to different patterns of susceptibility to tobacco. In addition, the influenza vaccine was effective in preventing hospitalization but was slightly less effective in smokers/ex-smokers than in non-smokers. The estimated risk of influenza hospitalization in patients with a history of smoking (aOR = 1.31) may be attributed to the effects of tobacco in ex-smokers aged ≥ 65 years. Similarly, we estimated in another study11 that the risk of hospitalization was slightly higher (aOR = 1.73) in ex-smokers aged ≥18 years although lower than in smokers (aOR = 2.18). Likewise, Ward et al.17 found that the risk of hospitalization remains very high in ex-smokers aged ≥16 years (aOR = 2.18). All these studies reported that the risk of hospitalization was greater, although less so, in ex-smokers, suggesting that the lesions caused by smoking remain over time, although their effects lessen. The risk of the history of smoking on influenza hospitalization remained in different age groups, with variations due to the low power of the analysis in some cases. There was an increased risk in patients with a history of smoking aged ≥ 85 years. Likewise, other studies suggest the increased risk in ex-smokers may be due to the cumulative effect of smoking over time.11,18 The risk of influenza hospitalization in patients aged ≥65 years with a history of smoking was greater in females than in males. The study by Kark et al.19 showed a higher risk ratio in female soldiers who smoked (RR = 1.44) than in those who did not, while Ward et al.17 reported a higher risk of influenza hospitalization in female former smokers of childbearing age (OR = 2.8). In contrast, other studies found a higher risk in male smokers than in female smokers and ex-smokers.11,17 As we only studied the history of smoking in patients aged ≥ 65 years, a possible survival effect in males and smokers cannot be ruled out, as women and never-smokers tend to live longer.16 Influenza vaccine effectiveness was moderate (21% in smokers and 39% in non-smokers), and was similar to that found in other observational studies in patients aged ≥ 65 years.20 Furthermore, influenza vaccination is strong recommended by the main public health agencies.21,22 The prevalence of smoking in controls was higher in non-influenza vaccinated patients than in vaccinated ones and suggests, similar to other studies, that a history of smoking may be negatively associated with influenza vaccination.23 Vander et al. found that, in the Behavioral Risk Factor Surveillance System of US adults, daily smokers were less likely to receive influenza vaccination despite their increased risk for respiratory disease.24 Our results are consistent with studies in animal models which found that smoking damages the immune system of the airways, causing a reduction in interferon gamma (IFN γ) and CD4 lymphocytes, thus enabling not only infection but also the severity of influenza.4,13,25 A cohort study26 in volunteer smokers, ex-smokers, second-hand smokers and non-smokers who were inoculated with an attenuated influenza virus in the nasal mucosa found not only suppression of the response to the virus but also a higher viral load in people exposed to smoking. It also found greater disease severity and persistence of the effect of smoking in ex-smokers. This study has some limitations. Smoking consumption was collected through interviews and the history of smoking was self-reported by patients. However, as all patients, cases and controls were hospitalized and as a structured questionnaire was used, potential observer bias was minimized. We also matched cases and controls for the date of hospitalization ± 10 days, to avoid recall bias or other errors associated with the moment patients contacted the health system. Some risk factors were related to age. We matched cases and control by age ± 3 years to control for the effect of age and to obtain a sufficient number of controls for logistic reasons. In cases and controls, the prevalence of smoking decreased with age and was much higher in males than in females. Therefore, the risk in some subgroups (males and younger adults) may have been diluted by the possible confounding effect of sex and age.16 For this reason, we also estimated the risks using separate regression models according to gender and age group. The outcome measure used in this study was hospitalization due to influenza, and smoking is also associated with an increased risk of other factors that influence hospitalization, including the marital status, high alcohol consumption, the Barthel index and chronic diseases including COPD, diabetes, congestive heart disease and renal failure.15,27 However, all these variables were entered in the final regression models and their effects controlled for, but residual confounding cannot be ruled out. The results of this study have implications for public health. The fraction of the risk of influenza hospitalization attributable to smoking was 24.2% in smokers and ex-smokers aged ≥65 years, slightly lower than the 40.6% found by Kark et al.,9 and suggests that patients with a history of smoking should be informed about their risk of hospitalization due to influenza. Likewise, studies have shown lower rates of influenza vaccination in smokers23,28 which could add to the negative effect of smoking. The effectiveness of influenza vaccination in our study was slightly lower in smokers than in non-smokers. Horvath et al. found that cytotoxic NK cell activity and IFNγ levels were suppressed in smokers following live attenuated influenza vaccination.29 However, Woolpert et al. studied 28 929 vaccination events during two influenza seasons, including 22 734 (79%) live attenuated vaccinations and 6195 (21%) trivalent inactivated influenza vaccinations, and found that, in the final adjusted model, the relative effectiveness of the two vaccine types did not differ by smoking status (P = 0.10).30 Other studies have shown a high effectiveness of influenza vaccination in vaccinated smokers compared with non-vaccinated smokers.23 Therefore, smoking should be an indication for vaccination for current smokers and ex-smokers, as suggested by the Centers for Disease Control and Prevention for the 23-valent pneumococcal polysaccharide vaccine.31 In conclusion, a history of smoking may increase the risk of hospitalization in smokers and ex-smokers. Preventing smoking could reduce hospitalizations due to influenza. Smokers and ex-smokers should be informed of the risk of hospitalization due to influenza infection, and encouraged to stop smoking. Smokers should be considered an at-risk group to be aggressively targeted for routine influenza vaccination. Supplementary data Supplementary data are available at EURPUB online. Acknowledgements The other members of the CIBERESP Cases and Controls in Pandemic Influenza Working Group are: Andalusia: J. Díaz-Borrego (Servicio Andaluz de Salud), A. Morillo (Hospital Universitario Virgen del Rocío), M.J. Pérez-Lozano (Hospital Universitario Virgen de Valme), J. Gutiérrez (Hospital Universitario Puerta del Mar), M. Pérez-Ruiz, M.A. Fernández-Sierra (Hospital Universitario San Cecilio y Virgen de las Nieves), M.A. Fernández-Sierra (Complejo Hospitalario Universitario de Granada); Castile and Leon: S. Tamames (Dir. General de Salud Pública, Investigación, Desarrollo e Innovación, Junta de Castilla y León), S. Rojo-Rello (Hospital Clínico Universitario de Valladolid), R. Ortiz de Lejarazu (Universidad de Valladolid), M.I. Fernández-Natal (Complejo Asistencial Universitario de León), T. Fernández-Villa (GIIGAS-Grupo de Investigación en Interacción Gen-Ambiente y Salud, Universidad de León), A. Pueyo (Hospital Universitario de Burgos); Catalonia: A. Vilella (Hospital Clínic), M. Campins, A. Antón (Hospital Universitari Vall d’Hebron; Universitat Autónoma de Barcelona), G. Navarro (Corporació Sanitària i Universitaria Parc Taulí), M. Riera (Hospital Universitari MútuaTerrassa), E. Espejo (Hospital de Terrassa), M.D. Mas, R. Pérez (ALTHAIA, Xarxa Hospitalaria de Manresa), J.A. Cayla, C. Rius (Agència de Salut Pública de Barcelona; CIBERESP), N. Torner (Agència de Salut Pública de Catalunya; Universitat de Barcelona; CIBERESP), C. Izquierdo, R. Torra (Agència de Salut Pública de Catalunya), L. Force (Hospital de Mataró), I. Crespo (Universitat de Barcelona; CIBERESP); Madrid: M.F. Domínguez-Berjon, M.A. Gutiérrez, S. Jiménez, E. Gil, F. Martín, R. Génova-Maleras (Consejería de Sanidad), M.C. Prados, F. Enzzine de Blas, M.A. Salvador (Hospital Universitario la Paz), J.C Galán, E. Navas, L. Rodríguez (Hospital Ramón y Cajal), C.J. Álvarez, E. Banderas, S. Fernandez (Hospital Universitario 12 de Octubre); Navarra: J. Chamorro (Complejo Hospitalario de Navarra), I. Casado, J. Díaz (Instituto de Salud Pública de Navarra); The Basque Country: M.J. López de Goicoechea (Hospital de Galdakao); Valencia Community: F. Sanz (Consorci Hospital General Universitari de Valencia). Funding This study was funded by the National Plan of I + D+I 2008–2011 and ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Project PI12/02079) and cofunded by Fondo Europeo de Desarrollo Regional (FEDER. Unión Europea. Una manera de hacer Europa), and the Catalan Agency for the Management of Grants for University Research (AGAUR Grant number 2014/SGR 1403). This study was supported by the Ministry of Science and Innovation, Instituto de Salud Carlos III, Project PI12/02079. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflicts of interest: No author has any commercial or other association that might pose a conflict of interest. Key points Smoking was associated with an increased risk of influenza hospitalization due to influenza in the elderly. Smoking reduces influenza vaccine effectiveness in the elderly. Smoking prevention could reduce hospitalizations due to influenza. References 1 Horby P, Mai LQ, Fox A, et al.   The epidemiology of interpandemic and pandemic influenza in Vietnam, 2007–2010 The Ha Nam Household Cohort Study I. Am J Epidemiol  2012; 175: 1062– 74. 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The European Journal of Public HealthOxford University Press

Published: Feb 1, 2018

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