Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed to treat haematological malignancies since the 1960s. Unfortunately, pulmonary complications are frequent after this type of transplantation and are a major cause of post-transplant mortality.
Induced sputum (IS) and measurement of exhaled nitric oxide (FeNO) are non-invasive methods to investigate airway inflammation, which have been extensively used to assess airways inflammatory diseases. However, these procedures have not been studied in the context of HSCT.
In the first part of this work, in an attempt to detect modifications at airway level, we monitored lung function and airway inflammation in 182 patients who underwent HSCT. We prospectively measured FEV1, FVC, DLCO, KCO, TLC, RV, FeNO as well as sputum cell counts before and 3, 6, 12, 24 and 36 months after HSCT. We observed that there was a progressive loss in lung function after HSCT featuring a mild restrictive pattern while bronchiolitis obliterans rarely occurred (3.5%). Moreover, the patients undergoing a HSCT exhibited a high sputum neutrophil count, which was sustained over all the period of observation. By contrast, the FeNO value remained in the accepted normal range throughout the post-transplant course.
The myeloablative (MA) conditioning was associated with early rise of sputum neutrophils and greater alteration in lung function over the first year. Overall survival at 1 year after HSCT were 71% and none of the baseline functional and airway inflammation features had a prognostic value for survival at one year.
In a second part of our work, we measured Th1, Th2 and Th17 cytokines in the IS supernatant in order to better characterize the airway inflammatory process in patients with HSCT. Then, we compared the results with those from healthy subjects matched for age and tobacco habits and with patients suffering from chronic obstructive pulmonary disease (COPD), a chronic airway inflammatory disease also marked by a airway neutrophilic inflammation. We observed that that patients undergoing HSCT display raised sputum levels of IL-6 and IL-8 compared to healthy subjects though the levels remained lower than those found in COPD.
In the third part of our work, we assessed the impact of mesenchymal stem cell (MSC) co-infusion on lung function after HSCT. Indeed, MSC are used to promote engraftment and prevent graft-versus-host-disease in the context of HSCT but were shown to have opposite effects on lungs after systemic administration in animals. Their effects have never been studied in human after HSCT. Thus, we monitored lung functions, FeNO values, the occurrence of pulmonary infections and cytomegalovirus (CMV) reactivation in 30 patients who received an allogeneic unrelated HSCT after non-myeloabaltive (NMA) conditioning with MSC co-infusion. They were compared with 28 patients undergoing the same type of transplantation and conditioning but without MSC infusion. The impact of MSC on pulmonary infections and CMV reactivation was analysed by uni and multivariate Cox models adjusted for competing risks. The principal observations were that MSC were safe at lung level after HSCT and did not lead to lung function changes 1 year post transplantation. However, MSC could promote pulmonary infections involving the need for a close monitoring of their occurrence.
There was a progressive loss in lung function after HSCT, featuring a restrictive pattern. Myeloablative conditioning was associated with early rise of sputum neutrophils and greater alteration in lung function over the first year. Moreover, patients undergoing HSCT exhibited a neutrophilic airway inflammation associated with raised sputum levels of IL-6 and IL-8, a picture similar but developed to a lesser extent of what is seen in COPD.
Finally, MSC co-infusion did not induce pulmonary deterioration 1 year after HSCT with NMA conditioning. MSC appeared to be safe for the lung but close monitoring of pulmonary infections remains essential.