Birgitta Versluijs

170 Outcome determinants for allo-LS Risk factors for outcome were not studied profoundly. Supplemental oxygen require- ment and mechanical ventilation were found to be bad prognostic factors bij several authors. 8,41 These factors probably reflects more severe lung disease, with its logical im- pact on outcome. Our data confirm these findings and also showed that GvHD requiring systemic treatment and the presence of a respiratory virus (RV) at diagnosis of Allo- LS influence outcome. Allo-LS occurrence in a patient who already receives steroids for GvHD in another organ, apparently is more difficult to treat with mainly an increase of steroid dose. And if RV still plays a role in Allo-LS at time of diagnosis the chances for good long-term outcome are better. We would still recommend initial treatment with MP pulse in all patients developing Allo-LS. However, as treatment failure occurs frequent and so early after the initiation of therapy, second line therapy should be optimized and started early in the course of the disease. For IPS this could be the addition of TNF-alpha blockade. For BOS an advice on second line therapy is less obvious. What are the next steps in therapy development? Lack of efficacy and fear for side effects further drive research to develop new therapy strategies for allo-LS. The rationale of most ongoing clinical trials is based on pathophy- siology mechanisms. (See Figure 1 and Figure 2) And here again the parallel between Allo-LS after HCT and lung allograft rejection can be drawn, with IPS mimicking acute cellular or antibody mediated rejection and BOS regarded as the clinical correlate of chronic lung allograft dysfunction. 22,42 In IPS initial tissue damage secondary to conditioning regimen, infection or transfusi- ons leads to release of inflammatory cytokines (especially TNF-alpha and IL-6) and incre- ased MHC class I and II expression on antigen presenting cells (APC) and target tissue. Lipopolysaccharides (LPS), translocating from the intestines in case of gut damage by conditioning or GvHD, also seem to play a role in activating the innate HCT-donor im- munity (neutrophils and macrophages). All this contributes to T-cell activation, directing T-cell injury in the target cells. From experimental allo-HCT models we have learnt the importance of T helper-2 response, with low IFN-gamma and high IL-6, inducing Th17 cells accumulation and IL-17 production causing lung injury. 2,43,44 In IPS the only drug that has been studied in a clinical trial was Etanercept. Yanik et al have performed a double-blinded randomized trial in adults, adding Etanercept to corti- costeroid therapy. 45 The study showed no benefit of etanercept on early response (62.5% vs 66.6% )or overall survival (23.7% vs 16.7%) in IPS, partly because the control arm initially performed much better than historical experience. 9