Hiroyuki Takatsuka

Complications after bone marrow transplantation are manifestations of systemic inflammatory response syndrome

Bone marrow transplantation has been established as a useful treatment for various hematological disorders and is now performed widely, but the mortality rate is still high due to various complications. A clear therapeutic policy for such complications has not yet been established because of their complex nature. We investigated whether the major complications occurring after bone marrow transplantation could be classified as aspects of the systemic inflammatory response syndrome. Subjects were 10 patients who developed severe complications after bone marrow transplantation (graft-versus-host disease, thrombotic microangiopathy, respiratory disorders, and cytomegalovirus interstitial pneumonitis) and 16 patients without complications. Their symptoms, serum cytokines, and factors related to vascular endothelial damage were compared before and after transplantation. Whereas all 10 patients who developed complications had fever in the aplastic phase after transplantation, 15 of the 16 patients without complications remained afebrile (P < 0.001, t-test). When compared with the patients who did not develop complications, the patients with complications also showed significantly higher cytokine levels during the recovery phase after transplantation (P < 0.0001, t-test). Thus, the patients with complications developed fever in the aplastic phase and showed an increase of cytokines during the recovery phase, which triggered the occurrence of vascular endothelial damage shown by factors such as the thrombomodulin and plasminogen activator inhibitor type 1. This sequence of events corresponds with that occurring during systemic inflammatory response syndrome, so many of the complications of bone marrow transplantation can be considered as manifestations of this syndrome. Bone Marrow Transplantation (2000) 26, 419–426.

Elevated interleukin (IL)-18 levels during acute graft-versus-host disease after allogeneic bone marrow transplantation.

Acute graft‐versus‐host disease (aGVHD) after allogeneic bone marrow transplantation (BMT) is mediated by grafted T lymphocytes after their polarization into type 1 T cells. Interleukin (IL)‐18, a novel immunoregulatory cytokine, strongly stimulates type 1 T cells, therefore we postulated that IL‐18 may be involved in the pathogenesis of aGVHD. Using an enzyme‐linked immunosorbent assay (ELISA), we serially measured serum levels of IL‐18 in 37 patients with haematological malignancy before and after allogeneic BMT. Patients with aGVHD had high levels of IL‐18 that strongly correlated with the severity of aGVHD. We also found that they showed reduced serum levels of IL‐18 after appropriate treatment or at a state of resolution. IL‐18 levels were not affected by the pretransplant regimen, engraftment or bacterial infection. Compared with circulating interferon (IFN)‐γ or IL‐12 levels, serum levels of IL‐18 showed a more sensitive and specific correlation with the disease status of aGVHD. These findings suggest that IL‐18 may play important roles in the pathogenesis of aGVHD and that measurement of serum IL‐18 levels can be useful indicator of aGVHD.

Oral eicosapentaenoic acid for complications of bone marrow transplantation.

The ‘systemic inflammatory response syndrome’ (SIRS) may represent the underlying cause of complications after bone marrow transplantation (BMT). This study was conducted to determine whether blocking the etiologic factors of SIRS could improve the complications of BMT. Sixteen consecutive patients with unrelated donors were allocated alternately to two groups. Seven patients received 1.8 g/day of eicosapentaenoic acid (EPA) orally from 3 weeks before to about 180 days after transplantation, while nine patients did not. These two groups were compared with respect to complications, survival, and various cytokines and factors causing vascular endothelial damage. All seven patients receiving EPA survived and only two had grade III graft-versus-host disease (GVHD). Among the nine patients not receiving EPA, three had grade III or IV GVHD. In addition, thrombotic microangiopathy developed in four patients and cytomegalovirus disease occurred in four. Five patients died in this group. The levels of leukotriene B4, thromboxane A2, and prostaglandin I2 were significantly lower in patients receiving EPA than in those not receiving it (all P < 0.01). Cytokines such as tumor necrosis factor-α, interferon-γ, and interleukin-10 were also significantly decreased by EPA (P < 0.05), as were factors causing vascular endothelial damage such as thrombomodulin and plasminogen activator inhibitor-1 (P < 0.05). The survival rate was significantly higher in the group given EPA (P < 0.01). EPA significantly reduced the complications of BMT, indicating that these complications may be manifestations of the systemic inflammatory response syndrome. Bone Marrow Transplantation (2001) 28, 769–774.

Endothelial damage caused by cytomegalovirus and human herpesvirus-6

Summary:Infection with cytomegalovirus (CMV) or human herpesvirus-6 (HHV-6) may have a role in vascular endothelial damage after bone marrow transplantation (BMT). In total, 41 patients who underwent BMT were classified into four groups (12, 10, 7, and 12 patients who were infected with both CMV and HHV-6, CMV alone, HHV-6, and neither virus, respectively). Levels of thrombomodulin, plasminogen activator inhibitor-1, and cyclic GMP were 7.5±1.7 FU/ml, 76.4±24.1 ng/ml, and 9.51±1.1 pmol/ml, respectively, in the patients with both viruses, while the respective values were 2.9±0.67 FU/ml, 33.8±8.09 ng/ml, and 2.90±1.4 pmol/ml in patients infected with CMV alone, 4.8±0.96 FU/ml, 47.7±9.21 ng/ml, and 5.48±0.55 pmol/ml in patients with HHV-6 alone, and 1.6±0.39, 17.5±7.88 ng/ml, and 0.45±0.3 in those with neither virus. All three markers were significantly higher in the three groups with at least one virus than in the uninfected patients (P<0.05), and were also higher in patients with HHV-6 alone than in those with CMV alone (P<0.05). These results suggest that infection by CMV or HHV-6 causes vascular endothelial injury, with HHV-6 having a stronger effect than CMV, and combined infection having a stronger effect than either virus alone. Such viral infection may be a cause of thrombotic microangiopathy after BMT.

Predicting the severity of graft-versus-host disease from interleukin-10 levels after bone marrow transplantation.

Acute graft-versus-host disease (GVHD) is the most important complication of allogeneic bone marrow transplantation. We investigated the possibility of predicting severe acute GVHD using plasma interleukin-10 levels in 31 patients who underwent allogeneic bone marrow transplantation. In patients with acute GVHD, the interleukin-10 (IL-10) level increased significantly from the aplastic phase through the leukocyte recovery phase after transplantation (P < 0.05, paired t-test). The ratio of the IL-10 level in the aplastic phase to that in the leukocyte recovery phase was significantly correlated with the severity of acute GVHD (P < 0.05, t-test), and the incidence of grade III or IV disease was significantly increased (P < 0.0001). since il-10 antagonizes various other cytokines that induce acute gvhd, determination of the il-10 level is equivalent to assessing the total production of cytokines promoting gvhd. the ratio of the il-10 level in the aplastic phase to that in the recovery phase seems to be useful for predicting the subsequent risk of acute gvhd.

Intestinal graft-versus-host disease: mechanisms and management.

Allogeneic haematopoietic stem cell transplantation remains the treatment of choice for a number of malignancies. However, graft-versus-host disease (GVHD) has long been regarded as a serious complication of this procedure. Although GVHD may affect any organ, intestinal GVHD is particularly important because of its frequency, severity and impact on the general condition of the patient.Recent studies have led to progressive elucidation of the mechanism of GVHD. Donor T cells are critical for the induction of GVHD, because depletion of T cells from bone marrow grafts effectively prevents GVHD but also results in an increase of leukaemia relapse. It has been shown that the gastrointestinal tract plays a major role in the amplification of systemic disease because gastrointestinal damage increases the translocation of endotoxins, which promotes further inflammation and additional gastrointestinal damage. Consequently, the management of intestinal GVHD (and the intestine itself) is a subject that should be highlighted.In this article, approaches to the prevention of intestinal GVHD are discussed after being classified into three categories: regimens in common clinical use, regimens under investigation and original regimens used at our hospital. The standard regimen that is used most widely for prevention of GVHD is cyclosporin plus short-term methotrexate. Corticosteroids can be added to this regimen but careful consideration of the adverse effects of these hormones should be considered. Tacrolimus is a newer, more potent alternative to cyclosporin. T-cell depletion (TCD) after transplantation has been shown to prevent acute GVHD, however, the survival benefit of TCD has not been as great as expected. Mycophenolate mofetil can be useful for the treatment of acute GVHD as part of combination therapy. Regimens currently under investigation in animal experiments include suppression of inflammatory cytokines and inhibition of T-cell activation, and, specifically at our institution, hepatocyte growth factor gene therapy. The evidence-based therapy used at our institution includes systemic antibacterial therapy (including eradication of intestinal bacteria) to prevent the intestinal translocation of lipopolysaccharide and avoid the subsequent increase of various inflammatory cytokines. In addition, because of the similarities between intestinal GVHD and ulcerative colitis, sulfasalazine, betamethasone enemas and eicosapentaenoic acid have been used to treat intestinal GVHD in some patients.

Effects of total body irradiation on the vascular endothelium

Takatsuka H, Wakae T, Mori A, Okada M, Okamoto T, Kakishita E. Effects of total body irradiation on the vascular endothelium. Clin Transplant 2002: 16: .

Evaluation of CMV/human herpes virus-6 positivity in bronchoalveolar lavage fluids as early detection of acute GVHD following BMT: evidence of a significant relationship

We evaluated the relationship between CMV and human herpes virus-6 (HHV-6) reactivation and the incidence of grades 2 to 4 acute GVHD post BMT. Bronchoalveolar lavage fluid (BALF) samples extracted from 54 BMT recipients on post-BMT day 35 were analyzed by PCR for detection of CMV DNA, HHV-6 DNA and CMV plus HHV-6 DNA. CMV DNA was detected in 26 patients and 13 (50%) developed grades 2 to 4 acute GVHD. Of the 28 who were CMV negative, only six (21.4%) developed grades 2 to 4 acute GVHD. HHV-6 was detected in 18 patients, and 11 (61.1%) developed grades 2 to 4 acute GVHD. Of the 36 who were HHV-6 negative, only eight (22.2%) developed grades 2 to 4 acute GVHD. CMV and HHV-6 were detected in 13 patients, and eight (61.5%) developed grades 2 to 4 acute GVHD. Of the 23 who were negative for both CMV and HHV-6, only three (13%) developed grades 2 to 4 acute GVHD. In all experiments, the difference between the groups was significant (P < 0.05, P < 0.05 and P < 0.01, respectively). we conclude that herpes virus infection, in particular cmv concurrent with hhv-6 reactivation, is predictive of moderate to severe acute gvhd. Bone Marrow Transplantation (2000) 26, 77–81.

Reduced-Intensity Conditioning Followed by Unrelated Umbilical Cord Blood Transplantation for Advanced Hematologic Malignancies: Rapid Engraftment in Bone Marrow

Reduced-intensity (RI) conditioning followed by cord blood transplantation (CBT) is a new treatment modality, but failure to engraft is a major concern. We describe 12 patients with advanced hematologic malignancies who underwent RI conditioning and CBT with a conditioning regimen consisting of 200 mg/m2 fludarabine (Flu), 50 mg/kg cyclophosphamide (CY), and 3 Gy total body irradiation (TBI). Cyclosporin A and/or methotrexate were used for graft-versus-host disease prophylaxis. Cord blood grafts were not mismatched for more than 2 serologically defined HLA alleles but were later found by high-resolution DNA typing to be mismatched for 2 to 4 alleles in most cases. Short tandem repeat analysis of bone marrow cells at day 14 showed complete donor chimerism in 6 of the patients and mixed chimerism in 5, indicating rapid engraftment in the bone marrow, whereas the remaining patient experienced graft rejection. Neutrophil recovery was achieved at a median of day 17 (range, days 11-24) in 10 of the 11 patients with marrow chimerism at day 14. Of these 10 patients, however, transplantation-related mortality within 100 days occurred in 4 patients who showed failed platelet recovery and a lack of durable engraftment. Overall survival and disease-free survival rates were 41.7% and 33.3%, respectively.These results show that CB mismatched at 2 to 4 HLA alleles and transplanted with the Flu/CY/3 Gy TBI regimen is able to engraft in the bone marrow as early as day 14.

Increased hepatocyte growth factor in serum in acute graft-versus-host disease.

Hepatocyte growth factor (HGF) was reported to be effective in preventing acute graft-versus-host disease (GVHD) in a murine model. We examined serum HGF concentrations in 38 patients receiving allogeneic bone marrow transplants, and investigated the relationship of serum HGF concentrations to severity of acute GVHD. More HGF was present in sera from patients with than without acute GVHD. Serum HGF correlated significantly with grade of acute GVHD. Furthermore, serum HGF correlated with serum concentrations of C-reactive protein, γ-glutamyltranspeptidase (GTP), and aspartate aminotransferase (AST). Serum concentrations of HGF in transplanted patients without GVHD were consistently low, while those in patients with acute GVHD increased with exacerbation. We conclude that HGF was produced during induction of the GVH reaction, and probably increased as a physiological response. Bone Marrow Transplantation (2001) 28, 197–200.