Birgitta Versluijs

120 Discussion The respiratory microbiome, which consists of viruses, bacteria, and fungi, closely in- teracts with local and systemic immunity. Viral immunomodulation is complex and multidimen-sional. 21-23 There is growing interest in understanding how disturbances can lead to lung disease, especially in the field of chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). 21 Our data suggest that similar processes can occur because of common cold RV persistence in the lungs in immune-deficient patients while reconstituting a donor-derived novel immune system. This concept fits the current understanding of alloimmunity after HCT, where host antigen-presenting cells are activated by danger signals expressed on damaged tissues, pathogens, or both, leading to alloactivation and cytokine release and inducing a cycle of inflammation and tissue damage. 24-26 Therefore further studies on the influence of the microbiome/viriome on the development of alloreactive immune phenomena after HCT are of great interest. In line with this, in patients with an inborn error of metabolism, which was found to be a borderline predictor for IPS, storage of glycosaminoglycans in the lungs can lead to low-grade inflammation and activation of antigen-presenting cells as well. The effects of viral infection and inflammation have been studied in other allograft set- tings. In lung transplant recipients several groups have found an association between RVs and the development of acute and chronic allograft rejection and BOS, the main limitation to long-term survival. 5,27-29 Also, in patients receiving other solid-organ trans- plants, there is evidence of infection playing a role in allograft dysfunction both through immunologic factors and nonimmunologic components. 30 In a recent study on RVs and IPS after HCT, Seo et al 31 described that when using cur- rently available diagnostic methods, in retrospect, they found occult pathogens in the majority of BAL fluid samples taken at diagnosis from patients with IPS. The presence of a pathogen was associated with mortality, even for pathogens with uncertain pulmo- nary pathogenicity, such as rhinovirus. They reconsidered the diagnosis, suggesting viral pneumonitis instead of IPS, and pointed out the possible harmful effect of high-dose steroids in case of detectable pathogens. This is in contrast with the interpretation of our findings. An important difference with our study is that Seo et al have no information on the RV status of the patients before they experience IPS. We have shown that in our pediatric population allo-LSs develop at a median of 8 weeks after first detection of RV (during T-cell reconstitution). Therefore we believe that it is not the RV itself that causes the respiratory deterioration but the inflammatory response (similar to immune reconstitution inflammatory syndrome in patients with HIV/AIDS). Timing of symptoms, protection by immunosuppressive therapy (in case of GVHD), and initial response to an increase in immunosuppression support our hypothesis of a primary immune-mediated process. On the basis of these results, we would recom- 7