Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview

Abstract

Mucositis is an inevitable side-effect of the conditioning regimens used for haematopoietic stem cell transplantation. The condition is better referred to as mucosal barrier injury (MBI) since it is primarily the result of toxicity and is a complex and dynamic pathobiological process manifested not only in the mouth but also throughout the entire digestive tract. A model has been proposed for oral MBI and consists of four phases, namely inflammatory, epithelial, ulcerative and healing phases. A variety of factors are involved in causing and modulating MBI including the nature of the conditioning regimen, the elaboration of pro-inflammatory and other cytokines, translocation of the resident microflora and their products, for example, endotoxins across the mucosal barrier, exposure to antimicrobial agents and whether or not the haematopoietic stem cell graft is from a donor. Neutropenic typhlitis is the most severe gastrointestinal manifestation of MBI, but it also influences the occurrence of other major transplant-related complications including acute GVHD, veno-occlusive disease and systemic infections. The pathobiology, clinical counterparts and the means of measuring MBI are discussed together with potential approaches for prevention, amelioration and, perhaps, even cure. Bone Marrow Transplantation (2000) 25, 1269-1278.

Figure 1

The relationship between oral mucositis and neutrophil counts of allogeneic haematopoietic stem cell transplant recipients. Twenty-eight patients received idarubicin, cyclophosphamide and TBI 9 Gy as conditioning therapy for an allogeneic haematopoietic stem cell transplant. The course of mucositis closely mirrors that of neutropenia. Donnelly et al⁵ 1992.

Figure 2

Mucosal barrier injury. Mucosal barrier injury occurs in four phases. The first phase is the inflammatory/vascular phase and is characterised by the induction of pro-inflammatory cytokines IL-1, TNF-alpha and IFN-gamma by cytotoxic drugs and irradiation while the epithelial cells are still intact. The second phase is the epithelial phase when cells cease dividing and die. This coincides with neutropenia. The third phase is when necrosis and ulceration occur and is when the resident microbial flora and their products, eg endotoxin translocate into the bloodstream. Moreover, impaired local defences and lower levels of secretory IgA may allow local infection to develop. The final phase is when healing takes place and involves the action of naturally occurring substances including trefoils, EGF and TGF. The events that take place in the gut are almost certainly more complicated than those occurring in the oral cavity since the gastrointestinal tract is intrinsically more complex in terms of its function, it possesses the specialised gastrointestinal-associated lymphoid tissue (GALT) system, and its resident microflora are more numerous and varied.