Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients

Abstract

Summary:We noted a significant increase of interleukin-8 (IL-8), LBP and CRP mirroring the pattern of mucosal barrier injury as measured by gut integrity (lactulose/rhamnose ratio), daily mucositis score (DMS) and serum citrulline concentrations of 32 haematopoietic stem cell transplant (HSCT) recipients following intensive myeloablative therapy. Concentrations of IL-8, LBP and CRP were already significantly elevated before the onset of fever or bacteraemia due to oral viridans streptococci (OVS) in the first week after transplant during profound neutropenia. These markers reached their peak when citrulline concentrations reached their nadir, the highest scores of DMS were attained and when there was significantly decreased gut integrity. This suggests that the degree of mucosal barrier injury rather than bacteraemia due to OVS determines the intensity of the inflammatory response. 1 It begins immediately after starting anticancer therapy with the activation of the nuclear transcription factor NF-kB resulting in the production and release of proinflammatory cytokines by various cells including lymphocytes, macrophages, endothelial cells and gut epithelial cells.2,3 Gut epithelial cells produce not only proinflammatory cytokines like TNF-a, interleukin (IL)-1a and IL-6, but also the chemokines, monocyte chemoattractant protein-1 (MCP-1) and IL-8, antimicrobial peptides (defensins, cathelicidins, lactoferrin) and the acute phase protein, LPS-binding protein (LBP).3-5 The release of proinflammatory cytokines and the blocking of clonogenic epithelial stem cell renewal results in apoptosis and necrosis, which manifests itself as epithelial atrophy and ulcerative lesions.6 The latter are a potential portal of entry for oral viridans (alpha-haemolytic) streptococci (OVS), which are universal commensals of the oral cavity placing haematopoietic stem cell transplant (HSCT) recipients at risk of developing bacteraemia due to these bacteria. 7 Our standard myeloablative regimen of idarubicin, cyclophosphamide and TBI to prepare patients for a T-cell depleted HSCT 8 is known to induce prolonged and severe MBI of the oral cavity and digestive tract.9 This is invariably accompanied by fever and bacteraemia due to frequent occurrence of viridans streptococci 10 as well as the continued release of C-reactive protein (CRP) (unpublished observation). We prospectively routinely determined CRP concentrations throughout admission of 32 HSCT recipients participating in a prospective randomised placebo-controlled study of glutamine-dipeptide-enriched parenteral nutrition and collected serum and plasma samples for measuring IL-8 and LBP later. We were particularly interested in investigating production of IL-8 and LBP together with CRP to determine the proinflammatory response of the gut during the process of MBI as defined by oral mucositis, sugar permeability tests (SPT) and serum citrulline concentrations. 11 Patients and methods PatientsA total of 32 patients (12 F; 20 M) with a mean age of 48 years (range 25-65) had given their in...

Febrile mucositis in haematopoietic SCT recipients

“…This has been previously observed in the setting of allogeneic HSCT. 19 It is consistent with a study on rats exposed to chemotherapy in which the release of pro-inflammatory cytokines was associated with evolving mucositis and preceded microbial translocation. 20 In addition, statistical analysis revealed a stronger association over time between citrulline levels and CRP than between bacteraemia and CRP, underlining a predominant role for mucositis in the occurrence of inflammation.…”

Bacteraemia coincides with low citrulline concentrations after high-dose melphalan in autologous HSCT recipients

“…17 Consequently, an increase in CRP levels may reflect the severity of gut mucosal damage. 4 All the episodes of bacteraemia that we observed were due either to coagulase-negative staphylococci or viridans Table 1 Mean ± 95% CI of citrulline concentrations, DMS, DGS, CRP and leukocytes on the first day of fever and total neutropenic days before the onset of fever in patients with neutropenic fever with or without bacteraemia streptococci. This is most likely a direct consequence of giving ciprofloxacin as prophylaxis, which effectively prevents bacteraemia due to Gram-negative bacilli, while giving selective advantage to the less susceptible Grampositive bacteria.…”

“…These levels also corresponded to the severity and extent of gut injury. 4 We explored the kinetics of citrulline concentrations in a cohort of patients treated with 200 mg/m 2 melphalan (Mel-200) to prepare for an autologous PBSC transplant (PBSCT). Furthermore, we determined the relationship of citrulline concentrations to bacteraemia, as the risk is known to be increased by mucositis.…”

Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis

“…Once again, a clear pattern of inflammation and fever was observed that coincided with the progression of MBI. There was a strong correlation between the extent of intestinal mucositis and the evolution of C-reactive protein, a biomarker of inflammation that correlates with pro-inflammatory cytokines such as IL8 (Blijlevens et al, 2005). The study included a group of patients who had received non-myeloablative conditioning, which caused very little intestinal mucositis, limited inflammation and a lack of bacteraemia, despite neutropenia lasting a median of 12 d. This provides evidence that the presence or absence of MBI determines to a large extent the early complications seen after SCT.…”