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

Abstract

Summary: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. Keywords: mucositis; mucosal barrier injury; diagnosis; risk factors; treatment Mucositis is an inevitable side-effect of the intensive conditioning therapy used for haematopoietic stem cell transplantation 1 and usually refers to the mucosal ulceration of mouth and throat. However, it is generally accepted that oral mucositis is in reality the most obvious manifestation of damage or injury elsewhere particularly that of the gut. Hence, mucosal barrier injury (MBI) may be a more appropriate term for this biological process. There exists no clear definition of MBI which is defined by a constellation of signs and symptoms that vary in their clinical expression. Oral MBI is reported to affect 60% to 100% of transplant recipients 2,3 and is characterised by pain, oedema, erythema, lesions, pseudomembrane formation, excessive mucous production, reduced saliva and bleeding, all of which reduce the patient's ability to eat and drink. In contrast, there are no reliable data on the incidence of gut MBI although intestinal symptoms affect almost every transplant recipient to some extent and include nausea, vomiting, abdominal cramping and watery diarrhoea occasionally accompanied by macroscopic blood loss. The exact course and severity of bowel symptoms of MBI are also difficult to ascertain because many patients are in such pain due to oral MBI that they only gain relief from narcotic analgesia which induces constipation as a result of reduced gut motility. There are also a number of scoring systems for oral MBI 4 although none is universally accepted and all lack standardisation. As yet, there is no system for registering gut MBI although there are published definitions for grading toxicity o...

Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation

“…[1][2][3][4][5][6][7] This reduced extrahematologic toxicity may lead to a reduction in infectious complications post transplant, since disruption of the gastrointestinal mucosa and/or damage to other key organs is a significant triggering mechanism of many of the infections that occur post transplant. 8,9 On the other hand, graft-versus-host disease (GVHD) and its treatment has a profound negative impact on immune reconstitution following HSCT, 10 and the impact of RIC regimens on the risk of acute and chronic GVHD is currently uncertain. The potential benefit on the risk of early infections derived from reduction of the intensity of the conditioning regimen may be negated by the immunodeficiency resulting from GVHD and its therapies.…”

The Prospective Oral Mucositis Audit: relationship of severe oral mucositis with clinical and medical resource use outcomes in patients receiving high-dose melphalan or BEAM-conditioning chemotherapy and autologous SCT

“…2,13 However, infection frequently cannot be documented in febrile patients. An alternative hypothesis is that fever may be a manifestation of the inflammatory process that is induced by conditioning chemotherapy 2,[15][16][17] and driven by acute phase cytokines such as tumour necrosis factor a (TNF-a) and interleukin 6 (IL-6). 17,18 Mucositis itself is also a potential source of local and systemic cytokines.…”

Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

“…The several complications, i.e. vomiting, nausea and mucosal barrier injury (Sonis, 1998;Blijlevens et al, 2000) result from loss of integrity of the intestinal barrier which is a key element in preventing inappropriate uptake and transport of macromolecules, bacteria and enteric toxins. To date, there is still no validated method to treat the side effects of anti-cancer treatment.…”