This is the first study to explore the early changes in lung function and pulmonary inflammation in a cohort of individuals who had undergone an allogeneic hematopoietic stem cell transplant. Our data demonstrate that lung function decreases and pulmonary inflammation increases after receiving an allogeneic HSCT. The change in exhaled nitric oxide may have potential in the stratification of patients for subsequent risk of mortality, and we consider that this is worth consideration in future cohort studies assessing potential biomarkers in this patient group.
One strength of our data is its high response rate, with 94% of eligible patients being enrolled in the cohort and only 6% of eligible patients declining to provide data. We were subsequently able to follow up the patients and collect detailed information on their changes in lung function and pulmonary inflammation, and also collect data on potential confounding factors and mortality. As our measurements were collected by a single person in a standardised manner, we are confident in that we have minimised the bias that can be introduced by multiple observers collecting data. The collection of data from a single centre which all patients who live in the surrounding centre attend ensures that the mortality data is complete.
Our study has a variety of limitations that require consideration. Having elected to collect detailed data on lung function and pulmonary inflammation, the study necessarily had to be from only one transplant centre due to staffing constraints. This has limited the number of participants that we were able to recruit and hence the power of the study to detect clinically important associations. However, this is the largest study to measure lung function and pulmonary inflammation in this patient cohort during the early months after receiving an allogeneic HSCT, and the 95% confidence intervals in our data should be useful in guiding researchers and clinicians in the future of the potential of these outcome measures in managing these patients. Unfortunately, we were unable to collect more detailed data on lung function including transfer factor due the logistical challenges of doing time-intensive measurements in a group of patients who are already debilitated from the HSCT. The generalisability of these data should be good for populations that are similar in age, initial disease and HSCT treatment regimens. As we have a relatively small study population and have tested a number of hypotheses, we are unable to exclude the possibility that some of the apparently significant associations observed may be spurious as a consequence of multiple hypothesis testing.
Previous research on the impact of receiving an allogeneic HSCT has tended to use routinely collected data at clinic visits, which is a powerful approach allowing over time large numbers of data to be collected. The largest previous study by Chien et al. demonstrated that new airflow obstruction (as defined as a more than 5% annual decline in FEV1 with the lowest post-transplant FEV1/FVC ratio of less than 0.8) was 26%, and associated with higher mortality rates at follow up than those with no airflow obstruction
. However, this important study did not look at pulmonary function tests within 6 months of receiving a HSCT, and hence is not directly comparable with our data. Savani et al. studied patients who survived for five years or more after HSCT, and reported that chronic graft-versus-host disease (GVHD) and low FEV1 and diffusion capacity for carbon monoxide were associated with a decrease in pulmonary function. As this study described a survivor cohort with a long follow up period, again direct comparisons with our data are impossible. Similarly, Lund et al. studied 43 patients who survived for five years and reported a decrease in lung function and transfer factor in the first year which returned to baseline after five years, and again these data are hence in a survivor cohort and not directly comparable to our data. A recent study looking at 33 patients, approximately one year after HSCT suggested that peripheral airways heterogeneity may be a better measure that could be more sensitive than simple lung function measurements such as FEV1 in detecting early lung pathology
To our knowledge no other studies have looked at the impact of receiving an allogeneic HSCT on pulmonary inflammation in adults in the six months after the procedure. The increase in pulmonary inflammation observed after HSCT may be a consequence of either the conditioning or the result of an immunological or inflammatory response to the allograft, and the absence of a consistent difference between the two conditioning groups suggests that the latter explanation may be more likely, although the study was not powered to examine these differences. The inverse association between change in exhaled NO from baseline at six weeks and three months with subsequent mortality was unexpected and needs to be considered with caution as the numbers of patients studied were small and these relationships may have occurred by chance as we have tested a number of associations in this analysis (p=0.04 to 0.06). Nonetheless, this is an interesting observation worth consideration. Exhaled nitric oxide is a measure of pulmonary inflammation
, and the inflammatory response in general probably evolved to help host organisms fight infection
. A recent study in 30 children with a mean age of 12 years suggests that higher exhaled nitric oxide is associated with pulmonary complications (predominantly infections) 28 days after receiving a HSCT
, demonstrating that this biological response is active in the early period after receiving a HSCT. Hence, we cautiously speculate that the inverse association between change in pulmonary inflammation and mortality observed in our dataset, if a true phenomenon, may be a consequence of an impaired ability to generate an inflammatory response, which may then result in increased susceptibility to infections in this patient group.
By adding to the literature of the relatively short-term consequences of receiving an allogeneic HSCT on the lungs, we have observed associations and hence generated hypotheses that now require consideration in other populations. The identification of biomarkers for pulmonary disease and mortality in individuals who have received an allogeneic HSCT is important as it will allow the early identification of those who are at high risk for these complications. This can then permit more intensive monitoring of this patient group and possibly also stratification to allow better targeted trials of interventions that can modify disease progression without exposing individuals who are less likely to develop these complications to the potential adverse side-effects that can accompany many therapeutic interventions.