The major finding of our study is that lifetime smoking dose is associated with an increased risk of respiratory failure within 100 days of transplant. This relationship appears to be only partially mediated by pre-transplant lung function, suggesting that other biologic mechanisms may be involved. We did not observe significant effects of smoking on overall relapse or non-relapse mortality, although the direction of the association between smoking dose and relapse warrants further investigation.
Few studies have examined whether cigarette smoking is a risk factor for poor transplant outcomes, and those have had conflicting results. Ho et al. found that smoking history, measured by smoking status (never, current, quit >1 year) was not associated with increased risk for early severe pulmonary complications, defined as diffuse alveolar hemorrhage, need for mechanical ventilation, or death from respiratory failure within the first 60 days post-transplant (11
). In contrast, a study done by Savani and colleagues reported that a history of smoking was associated with a 5-fold increase in risk of transplant-related mortality from pulmonary causes (13
). The latter, however, had a smaller cohort (n = 146), included patients diagnosed with idiopathic pneumonia syndrome, and followed patients for a median of 3.6 years (13
). The largest study by Marks et al., with 2,818 patients who received allogeneic transplants for CML in first chronic phase, found that the risk of treatment-related mortality was 57% higher among ≥ 10 pack-year smokers compared to never smokers (12
). In addition, such a smoking history was associated with increased risk of disease relapse, a finding consistent with a prior study by Chang et al. (10
). These findings, however, were observed only in recipients of HLA-identical sibling donor transplants (12
We also found an increased risk of relapse associated with smoking, although mainly among patients receiving an unrelated matched HSCT. These results should be considered preliminary, although in light of studies demonstrating that smoking increases the risk of hematologic malignancies, this may be biologically plausible (30
). The greater than two-fold increase in relapse risk among recipients of unrelated matched donors in our study may be partly attributable to our cohort having a higher underlying disease risk; we included a variety of underlying diseases that warranted allogeneic transplant as opposed to the cohorts in the Chang and Marks studies, which focused on CML in stable phase. Unlike the study by Marks et al., we did not find an association between smoking and non-relapse mortality, despite observing that 92% of patients who were placed on mechanical ventilation in the first 100 days after transplant ultimately died. It is possible that some patients with respiratory failure chose to forego mechanical ventilation prior to death. Alternatively, it is possible that smoking is not a risk factor for other common causes of non-relapse mortality such as acute or chronic GVHD and non-pulmonary organ toxicity or failure. There are several possible mechanisms for the association between smoking dose and early respiratory failure. Pre-transplant PFTs have been shown to be important predictors of early post-transplant pulmonary complications and mortality (5
). These parameters likely represent markers of previous lung injury and worse health status prior to transplant. In addition, cigarette smoking has immunomodulatory effects that have been linked to increased susceptibility to infection. The alveolar macrophages found in the lungs of smokers, for example, have a reduced ability to phagocytose bacteria and are known to secrete lower levels of inflammatory cytokines necessary for upregulation of host defenses (32
). Cigarette smoke may also have independent effects on mucociliary clearance and alterations in surfactant proteins (34
The strengths of our study include a large cohort, availability of detailed smoking history, and availability of PFTs near transplant. There are, however, important limitations to consider when interpreting our results. First, social desirability, especially prior to upcoming transplant, may have led to under-reporting of smoking. Although we do not have reason to believe this bias is differential among those who experienced respiratory failure or died, the effect would tend to bias our hazard ratios toward the null. Second, we could not assess whether smoking was continued or resumed during the post-transplant period, which may have affected our outcomes. Third, although there are no firm exclusion criteria with regard to PFTs, smoking status, or pulmonary disease for transplant eligibility at our center, patients with severe pulmonary and other co-morbidities may never have made it to transplant; thus, there could be selection bias. Despite these limitations, the findings that: 1) the vast majority of patients undergoing transplant have normal lung function, including former and current smokers (), and 2) an association remains between smoking dose and early respiratory failure independent of lung function, lends credence to our conclusion that cigarette smoking, even in patients without serious co-morbidities or compromised lung function, has independent deleterious effects after transplant.
In summary, our study found a significant association between cigarette smoking and respiratory failure within 100 days of transplant. This finding appears to be only partially mediated by abnormal lung function prior to transplant. While we found no significant association between smoking and relapse or non-relapse mortality after allogeneic HSCT, a trend was apparent, and future prospective studies with longer-term outcomes and ongoing monitoring of smoking status are warranted to explore this issue. We are not suggesting that HSCT should be withheld or delayed in patients with a smoking history in need of transplant; however, since cigarette smoking, identifies individuals at increased risk of early morbidity post-transplant, they should be counseled accordingly. Given the prevalence of smoking among HSCT cohorts, further studies should focus on tobacco cessation efforts in this patient population. In addition, they should evaluate the potential impact of length of quit time among former smokers and recent quitters on allogeneic transplant outcomes, as this could identify a window of opportunity for aggressive tobacco cessation interventions. This study also emphasizes the need for routine inclusion of smoking status and more detailed smoking history both prior to and after transplant in future HSCT studies.