Infection and GVHD

The role of infections in allogeneic stem cell transplantation and graft-versus-host disease has gained a renewed interest because of several developments in recent years. Variable degrees of immune deficiency exist as a consequence of immune suppression until the immune system of donor origin is established; graft-versus-host disease (GVHD) and immunosuppressive treatment for prophylaxis and therapy may delay the restoration. These conditions favor infections with various microorganisms. Several improvements in prophylaxis and treatment of infections as well as reduced intensity of the conditioning regimens and improved prophylaxis of GVHD have decreased toxicity of the treatment and transplant-related deaths. Improved antibiotics, antiviral and antifungal treatment have contributed to the greater success. However, infections with and without GVHD remain a major obstacle of allogeneic stem cell transplantation and immunotherapy. New diagnostic tools for the study of cytokines released during conditioning, the composition and alteration of the gut microbiome after transplantation and the innate immunity of the gut mucosa have given new insights into the pathophysiology of GVHD. The gut is a primary organ of T cell activation in acute GVHD; the incidence of GVHD is associated with a lower gut microbial diversity. The composition of intestinal microbiota seems to play an important role for the pathophysiology of intestinal GvHD. Commensal bacteria, particularly Clostridiales, like Blautia, have been shown to be associated with less GvHD. The mechanism by which anaerobic bacteria suppress GVHD is still unknown, most likely due to secretion of protective metabolites like short chain fatty acids or indole and its derivatives, thus exerting antiiflammatory effects and contribute to epithelial integrity and immunological homeostasis. Modulation of intestinal microbiota composition may influence the occurrence and severity of gut GvHD. The form of gut decontamination has also an important impact on GVHD. E.g., rifaximin is a broad-spectrum antibiotic with negligible gastrointestinal resorption that spares anaerobic bacteria and improves indoxyl sulfate production. Rifaximin preserves high microbiome diversity upon gut decontamination, as compared to ciprofloxacin and metronidazole being associated with less severe GI GvHD and improved survival. Even kind and timely use of systemic broad-spectrum antibiotics for therapy of neutropenic infections seems to impact gut GvHD. E.g., avoidance of imipenem/cilastatin and piperacillin/tazobactam seems to improve survival by decreasing GVHD rates, probably, due to growth of Akkermannsia muciniphilia with mucus-degrading capabilities, thus, probably, promoting intestinal inflammation and GvHD. Aztreonam and cefipime, both antibiotics with anaerobic sparing effects, may be preferable. Use of antibiotics before the day of transplantation may contribute to severe intestinal dysbiosis and poor outcome of patients after ASCT. The presence of certain strains of anaerobic bacteriae is associated with lower risks of GVHD and relapse of leukemia. Recent studies have shown that gut colonization with some strains of Blautia is associated with lesser risk of GVHD, and strains of Limus (Eubacteriaceae) is associated with a decreased relapse rate. This antileukemic mechanism is not well understood. A common finding is the production of short chain fatty acids. Hence, the question of total or selective gut decontamination is discussed controversially. Improved survival was described with the decontamination with rifaximin that is associated with surviving anaerobes and an increased production of indolsulfoxide. Treatment of GVHD of the gut has been attempted with the transfer of stool from a healthy person with some success. This may not only be the beneficial impact of bacteriae, but the composition of bacteriae with phages and other microorganisms. A recent study of the viriome found th The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs. There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.