Alveolar macrophage activity and the pulmonary complications of haematopoietic stem cell transplantation.

Abstract

Background--The success of haematopoietic (bone marrow or peripheral blood) stem cell transplantation (SCT) is compromised by pulmonary complications. We hypothesised that a proinflammatory alveolar microenvironment, reflected in alveolar macrophage (AM) cytokine production, would predispose to such complications.

Methods--AM were isolated from adult SCT recipients by bronchoalveolar lavage before SCT (n=32) and during post-transplant pancytopenia (n=23). Concentrations of tumour necrosis factor (TNF)[alpha], granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-l[beta], IL-6, and IL-8 in 24 hour AM culture medium were measured by enzyme linked immunosorbent assay and compared with both the occurrence of post-SCT lung disease and with subjects' previous respiratory histories.

Conclusions--Recent respiratory disease and persistent proinflammatory AM behaviour detectable before transplantation are associated with lung disease following SCT. These associations may prove useful in pre-transpla nt risk assessment.

Results--Eleven subjects developed lung disease within 6 months of SCT. These subjects had higher median pretransplant AM TNF[alpha] (8 (IQR 1-8) [upsilon] 2 (1-5) ng/[10.sup.6]AM, p=0.0l, median difference (D) = 3, 95% CI 0.1 to 7), GM-CSF (5 (0.7-8) [upsilon] 0.2 (0.1-0.8), p=0.006, D = 4, 95% CI 0.5 to 7), and IL-6 (0.5 (0.1-1) [upsilon] 0.1 (0.02-0.3), p=0.049, D = 0.3,95% CI 0.0002 to 1) production than remaining subjects; IL-1[beta] and IL-8 did not differ. During pancytopenia high AM GM-CSF production again predicted later lung disease (1(0.7-9) [upsilon] 0.1 (0.06-0.3), p=0.01, D = 1, 95% CI 0.1 to 6). A history of recent chest disease was associated with high AM TNF[alpha] and GM-CSF production and with post-SCT lung disease. Pre-SCT lung function was unrelated to post-SCT lung disease.

Keywords: haematopoietic stem cell transplantation; alveolar macrophage; cytokines

Marrow ablative cytotoxic therapy with autologous or allogeneic haematopoietic stem cell rescue (bone marrow or peripheral blood stem cell transplantation, SCT) is used increasingly in adults to treat haematological malignancy, solid tumours, and severe autoimmune disease, (1 2) but complications of the procedure limit its use. Lung diseases (infective, inflammatory, or idiopathic) are among the commonest complications: 11-60% of recipients develop lung disease following transplantation. The incidence varies according to transplant type and underlying disease, but reported case mortality is 40-60%. (3-5) A technique allowing pre-transplant estimation of the risk of post-transplant lung disease would therefore be clinically valuable.

In recipients of allogeneic bone marrow transplants, impaired gas transfer and increased bronchoalveolar lavage (BAL) fluid albumin levels before transplantation are associated with post-transplant pulmonary disease and mortality. (6 7) These measures were not predictive in individual cases, but the observations suggest that alveolar abnormalities before SCT may predispose to subsequent lung disease. We hypothesised that this predisposition may be detectable as proinflammatory alveolar immune cell behaviour. Unlike other alveolar immune cells, the resident alveolar macrophages (AM) survive marrow ablative cytotoxic therapy and persist for up to 90 days after allogeneic SCT. (8 9) We compared the proinflammatory behaviour of AM obtained from SCT recipients before transplantation and during post-transplant pancytopenia with the patients' clinical progress.

AM activity was defined using a panel of well characterised proinflammatory cytokines produced by AM and involved in infectious and inflammatory lung diseases: tumour necrosis factor [alpha] (TNF[alpha]), granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukins (IL)-1 [beta], IL-6, and IL-8. (10-12)

Methods

STUDY DESIGN

This prospective study was approved by Lothian health ethics committee. Adult patients attending Edinburgh's Western General Hospital Bone Marrow Transplant Unit for SCT were eligible; patients were excluded if the responsible clinicians judged them unfit for bronchoscopy and BAL. With informed written consent, subjects underwent fibreoptic bronchoscopy and BAL before starting the cytotoxic transplant conditioning regimen (B1) and again at the nadir of post-transplant pancytopenia (B2). Subjects were observed for new lung disease for 6 months after SCT. Proinflammarory cytokine production by AM…