The rate of current smoking within this sample was in the range reported in prior studies of HSCT candidates and survivors. Compared to patients with no history of smoking, current smoking was related to an average of 21 more days of hospitalization in an outpatient-based HSCT program in the first year post-HSCT. This translates to average hospitalization charges that are $126,434 higher per patient in the first year post-HSCT, based on national average charges for hospitalization with leukemia as primary diagnosis.19
Current smoking was associated with worse pre-transplant pulmonary function tests, which may have contributed to increased hospitalization days. These finding suggests that current smoking is a risk factor for poorer health status and may impair recovery from HSCT. Demographic factors associated with former smoking status among HSCT patients were similar to those found to predict tobacco cessation in the general population, including higher levels of social support (married) and older age. 6
Overall the current study supports the available literature documenting the negative impact of tobacco on HSCT outcomes. Marks and colleagues published the first study to observe a dose-response effect of lifetime smoking on mortality in a sample of 2818 patients treated for CML.12
Specifically they found a difference in treatment related mortality rates of 22% higher for “high dose” smokers (defined as a lifetime history of greater than both one pack per day and 10 pack-years) verses never smokers 5 years post-HSCT. Marks and colleagues also observed an 18% higher mortality rate and 25% lower disease free survival. Importantly, the Marks et al. observations persisted while controlling for a prognostic risk score. In our study, compared to never smokers, current smokers had 18%, 27%, and 24% lower survival rates, respectively at 1-, 2-, and 3-years post-HSCT, consistent with Marks et al. However, this difference did not reach statistical significance possibly related to a smaller sample size. Hoodin and colleagues observed a link between smoking until diagnosis and mortality.15
Other HSCT studies have linked smoking to pulmonary complications and infection. Among a sample of predominantly leukemia survivors treated with allogeneic HSCT, smoking within 2 months prior to transplant was an independent risk factor for PTRM.11
In this group of 146 consecutive HSCT patients, 38% of smokers (defined as smoking within 2 months prior to transplant and having a 2 year history of smoking) and 5% of non-users developed Pulmonary Transplant Related Mortality. An autopsy study observed that smoking history was a predictor of diffuse alveolar damage among HSCT recipients, affecting 64% of patients with a smoking history versus 37% of patients without a smoking history. Notably, this study observed that 89% of deceased HSCT recipients had a pulmonary complication at autopsy, the majority of which were undiagnosed prior to death. 10
In our sample, death attributed to pulmonary toxicity or respiratory distress was documented for 6% of never smokers, 20% of previous users, and 26% of current users. Pre-HSCT pulmonary function was significantly worse for smokers in our study, and is thus a likely contributing factor to pulmonary damage and mortality in the above studies. A study of 367 consecutive multiple myeloma survivors treated with autologous HSCT revealed pre-transplant smoking as an independent risk factor for infection, with 37% of current smokers versus 27% of former/never smokers developing a post-HSCT infection.13
In our sample, death attributed to infection was documented for only 9 participants (11% of never smokers, 8% of previous smokers, and 5% of current smokers).
Short-term studies are rare and do not support a link between smoking and early HSCT complications. A retrospective chart review of 339 consecutive HSCT recipients (mixed disease) revealed an 8-9% increased risk for severe pulmonary complications within 60 days post-transplant among patients with a history of cigarette smoking, 7
but it did not reach statistical significance. A study of sinusitis in 100 HSCT patients undergoing allogeneic transplant did not find a significant difference in frequency of dichotomous sinusitis variables (clinical disease severity, CT scan opacity) associated with history of smoking.8
Given the paucity of short-term outcome studies, further research is warranted.
Strengths of the current study include a consecutive patient sample with complete data on smoking, baseline pulmonary function tests, and the novel study context of an outpatient-based program that allowed for examination of hospitalization as a study outcome. To our knowledge, ours is the first study to examine duration of cessation in relation to HSCT outcomes. It is also the first to document a significant relationship between smoking and duration of hospitalization. Another strength of our study is use of a standardized coding system and multiple raters to minimize bias related to patient-report and health care provider-report methodologies, yielding smoking prevalence estimates congruent with large general population-based studies that are expected to approximately match true HSCT smoking prevalence rates. Limitations of this study include reliance on patient-reported smoking status (as all other cited studies) and medical records as source documentation (as all other studies besides one).9
Medical records were not available for hospitalizations outside our transplant center, thus hospitalizations outside our transplant center were not included in study analyses. However, there was not a significant association between in-state residence and smoking status. Detailed information regarding reasons for hospitalization, post-transplant complications, types of infection, cytogenetic risk, graft verses host disease, and prognostic scores were not recorded in a standard manner amenable to data abstraction. Tobacco quantity and frequency information was not generally recorded in the medical record, and thus dose-response relationships between tobacco and HSCT outcomes were not testable.
The scientific literature documenting a link between tobacco and adverse medical outcomes presents possible mediating mechanisms to explain the effects of tobacco on HSCT outcomes. Smoking is associated with reduced immune functioning (e.g., natural killer [NK] cell activity), increased pro-inflammatory cytokines that may predispose patients to both respiratory and systemic infections, 20
and comorbidity. 21
This suggests even greater risk for patient groups such as HSCT that experience compromised immunity.
Theoretically, tobacco cessation might improve HSCT outcomes, as has been demonstrated in tobacco-related cancer populations (e.g., survival22
) and is suggested by the significant association of current smoking to hospitalization in our study. Accounting for smoking in program statistics may improve estimates of risk for individual patients. Finally, if replicated and disseminated, the effect of tobacco on HSCT outcomes may motivate more patients and their providers to pursue appropriate tobacco cessation interventions, increasing tobacco abstinence rates. An association between duration of smoking cessation and outcomes may also motivate cessation as early as possible in patient care.
To our knowledge, ours is the first study observing an association between smoking and longer duration of hospitalization in HSCT patients. This is also the first study to associate current smoking with adverse HSCT outcomes. A need exists for prospective cohort studies examining the impact of smoking on HSCT outcomes. Future studies would be improved by standardized assessment and documentation of smoking status, a practice that is congruent with suggested practice guidelines.6
In particular, lifetime quantity of smoking (pack-years) and duration of cessation would allow examination of potential dose-response relationships between tobacco amount, cessation time, and HSCT outcomes. Future research should include a broader range of patient outcomes, including quality of life, return to work, health care related costs, and fatigue. Additionally, assessment of potential mediators such as NK-cell activity, pro-inflammatory cytokine levels, and standardized comorbidity scores might reveal mechanisms underlying relationships between smoking and HSCT outcomes. Lastly, barriers to tobacco cessation, including patient cognitive beliefs,2
motivational readiness, social support, and secondhand smoke exposure6
should be assessed to promote development of interventions that are viewed by patients as relevant and integrated into their clinical care.