Major Transplant-related Complications Research Articles

Haploidentical hematopoietic stem cell transplantation with busulfan, cyclophosphamide, and fludarabine conditioning for X-linked adrenal cerebral leukodystrophy.

We investigated the safety and efficacy of haploidentical stem cell transplantation (SCT) in pediatric patients with X-linked adrenoleukodystrophy (ALD). A retrospective analysis of transplantation data from 29 cases of ALD, treated between December 2014 and April 2022, was conducted. Neurologic function scores (NFS) were assessed. The conditioning regimen was busulfan 9.6 mg/kg, cyclophosphamide 200 mg/kg, and fludarabine 90 mg/m2 (BFC). Graft-versus-host disease prophylaxis consisted of anti-human thymocyte globulin, cyclosporine A, mycophenolate mofetil, and short course of methotrexate. Among the 29 cases, 14 cases (NFS = 0) were asymptomatic, and 15 (NFS ≥ 1) were symptomatic. The median age at SCT was 8 years (range: 4-16 years); the median follow-up time was 1058 days (range: 398-3092 days); 28 cases were father donors and 1 case was a grandfather donor. Hematopoietic reconstitution was successful in all patients, and all of them achieved complete donor chimerism at the time of engraftment. The leading cause of death was still primary disease progression (n = 4). Survival free of major functional disabilities was 100% in asymptomatic patients versus 66.67% in the symptomatic group (p = .018). BFC regimen used in haploidentical SCT was administered safely without major transplant-related complications even in symptomatic patients, and neurological symptoms were stabilized after SCT.

Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy

ObjectiveThe prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. PatientsSixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). ResultsPrimary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16–91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. ConclusionAllogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.

Enteric Microbiome Markers as Early Predictors of Clinical Outcome in Allogeneic Hematopoietic Stem Cell Transplant: Results of a Prospective Study in Adult Patients.

BackgroundInfections and graft-vs-host disease (GvHD) still represent major, not easily predictable complications in allogeneic hematopoietic stem cell transplant (allo-HSCT). Both conditions have been correlated to altered enteric microbiome profiles during the peritransplant period. The main objective of this study was to identify possible early microbiome-based markers useful in pretransplant risk stratification.MethodsStool samples were collected from 96 consecutive patients at the beginning of the pretransplant conditioning regimen (T0) and at 10 (T1) and 30 (T2) days following transplant. When significant in univariate analysis, the identified microbiome markers were used in multivariate regression analyses, together with other significant clinical variables for allo-HSCT-related risk stratification. Four main outcomes were addressed: (1) septic complications, (2) GvHD, (3) relapse of the underlying disease, and (4) mortality.ResultsThe presence of >5% proinflammatory Enterobacteriaceae at T0 was the only significant marker for the risk of microbiologically confirmed sepsis. Moreover, ≤10% Lachnospiraceae at T0 was the only significant factor for increased risk of overall mortality, including death from both infectious and noninfectious causes.Finally, a low bacterial alpha-diversity (Shannon index ≤ 1.3) at T1 was the only variable significantly correlating with an increased risk of GvHD within 30 days.ConclusionsMicrobiome markers can be useful in the very early identification of patients at risk for major transplant-related complications, offering new tools for individualized preemptive or therapeutic strategies to improve allo-HSCT outcomes.

Pentraxin 3 As a Novel Diagnostic and Prognostic Biomarker for Acute GvHD and Fungal Infections in Adult Allogeneic HSCT Recipients

BACKGROUND:Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity, involved in controlling infections and modulating inflammation, and acting as a new prognostic and diagnostic biomarker in these conditions. PTX3 has been recently recognized as an extrinsic oncosuppressor in cancer; its role in hematological malignancies and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is under investigation in both pediatric and adult settings.METHODS:From September 2012 we have conducted a prospective observational study to address the role of PTX3 in 35 adult patients affected by newly diagnosed AML (n=27) or ALL (8), and 73 adult pts who received allo-HSCT for acute leukemia. Stem cell donors were haploidentical (n=45), sibling (n=14), unrelated (n=14). Serial peripheral blood (PB) and bone marrow (BM) samples were collected from all patients. Time-points of sampling for leukemia patients included: diagnosis, relapse, any cycle of chemotherapy (CT; before starting and first day after the end), evaluation of treatment response (including BM), fever (first episode, or clinical suspicion of fungal infection). Samples from allo-HSCT patients were collected as following: before HSCT; at HSCT (day 0); day +7, day +14, 1 month (including BM), 2 months (including BM), 3 months (including BM) and 6 months (including BM) after HSCT; fever (first episode, or clinical suspicion of fungal infection); acute GvHD requiring systemic therapy (at onset or before starting a second line treatment, day+7 of treatment, then weekly during immunosuppressive therapy for 6 weeks). PTX3 level detection was performed with sandwich ELISA (detection limit 0.1 ng/ml).RESULTS:Firstly we analyzed the group of leukemia patients. Although PTX3 levels on PB at leukemia diagnosis were not influenced by patients (age, sex) or disease characteristics (type of leukemia, BM and PB blasts), they correlated with white blood cell counts (p=0,03). No statistical difference was found matching PTX3 levels at diagnosis with disease relapse or overall survival (OS). We did not observe any correlation between PTX3 levels before starting CT and response to treatment.When we moved to examine allo-HSCT patients, we observed an important difference in PTX3 levels on PB at day 0 among patients treated with treosulfan or busulfan-based conditioning (p=0,027). We found a trend towards an increase of PTX3 levels for patients who developed a subsequent GvHD at day +7, and for patients who received ATG instead of PT-Cy at day +14 (p =0,06 for both of them).Moreover, we evaluated 38 events of acute GvHD. Interestingly, PTX3 levels on PB at GvHD onset predict a subsequent evolution to chronic GvHD (p=0,02), also confirmed by ROC analysis (AUC 0.786) which allowed us to identify a threshold of 58 ng/ml (sens 75%, spec 85%). At day +7 from the start of therapy, PTX3 levels were correlated directly with steroid-refractory GvHD (p=0,004) and reflare (p=0,024), and inversely with GvHD resolution (p=0,003). Concomitantly, the ROC analysis identified a threshold of 18 ng/ml as predictor for steroid-resistance (AUC 0,91; sens 75%, spec 85%) and GvHD resolution (AUC 0,848; sens 70%, spec 85%).Finally, we reported 142 infectious events. No difference in PTX3 levels was reported for first and subsequent episodes, or with bloodstream infections. Importantly, in presence of invasive fungal infection (IFI), the levels of PTX3 were significantly increased (p=0,016).CONCLUSIONS:PTX3 is an early biomarker for major transplant-related complications, as IFI and acute GvHD. This study suggests that PTX3 is able to predict GvHD resolution and the risk of subsequent chronic GVHD development; moreover PTX3 predicts steroid-refractory GvHD, offering a new tool in pindividualized clinical management. DisclosuresCiceri:MolMed SpA: Consultancy.

Longitudinal Microbiome Profile in Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Prospective Study in 100 Patients

BACKGROUND: Allogeneic HSCT (allo-HSCT) is the only cure for several patients with hematological malignancies. Recent advances in therapies have significantly reduced transplant-related mortality (TRM); nevertheless infections and graft-versus-host disease (GvHD) still represent major complications. Recent studies indicate that patients undergo dramatic alterations of intestinal microbiota during allo-HSCT, potentially affecting the outcome. An alarming emergence of gram-negative multi-drug-resistant (GN-MDR) pathogens has been increasingly reported from various cancer centers, and the primary site of colonization is mainly the gut. Moreover, GvHD was associated with major shifts in the composition of intestinal microbiota, able to modulate the severity of intestinal inflammation.METHODS: Between October 2014 and March 2016, we have conducted a prospective observational study to examine the intestinal microbiota by NGS techniques in 100 consecutive adult patients, who received allo-HSCT for high-risk hematological malignancies (63.5% acute leukemia). Stem cell donors were family haploidentical (n=45), HLA identical sibling (n=15), unrelated volunteer (n=35), cord blood (n=5). Stem cell source was mainly T-cell replete PBSCs. Fecal specimens have been collected before conditioning (T0), during aplasia (T10) and after engraftment (T30). The fecal microbiome have been analyzed using the 454 GS Junior System, and QIIME software. We defined a threshold of normality for the main phyla on the basis of the control.RESULTS:We observed an important difference in relative percentages of phyla populating the gut between our pts and control. Our patients showed a progressive reduction of the intestinal microbial diversity (alpha diversity) during the transplant process, with a specific decrease of anaerobic species belonging to both Bacteroidetes and Firmicutes phyla, and a relative increase of facultative anaerobic gram-positive families such as Enterococcaceae and Staphylococcaceae. A great variation was observed, particularly between T0 and T30, where we found a significant decrease in alpha diversity (p < 0.001).A significantly different distribution in the baseline microbiome was reported in patients who will experience different clinical outcomes. Patients (n=23) who developed a microbiologically-confirmed sepsis show an increase of Proteobacteria phylum (cut-off 5%; p<0.01, RR= 5.38), and a decrease in Lachnospiraceae (cut-off 10%; p 0.02 and RR=2.77). Sepsis by GN-MDR bacteria (n=15) was strongly associated to an increase of Proteobacteria phylum (p<0.01 and RR=5.38 at T0). Microbiome changes preceded the development of severe sepsis and septic shock in 21 patients (increase of Proteobacteria, p 0.01 and RR= 2.43), underlying its potential for the prediction of these clinically relevant conditions and its impact on overall survival (increase of Proteobacteria p<0.01 and RR= 2.69; decrease in Lachnospiraceae, p<0.01 and RR=2.83).We identified by multivariate analysis some associations between the relative increase of a specific phylum and clinical variables at baseline. Previous allo-HSCT and prior infections represented strong risk factors for developing colonization by Proteobacteria (exceeding 5%). Sepsis by GN-MDR bacteria was associated to increase in Enterobacteriaceae(exceeding 5%; p 0.011).Interestingly, significant microbioma changes were observed at 10 days after transplant, in patients who developed a subsequent acute GvHD, with a predominant role played by gram-positive bacteria belonging to Firmicutes. More in details, the presence of Lachnospiraceae was associated to a decreased risk of developing acute GvHD (p=0.04 and RR= 4.35), whereas dominance of Enterococcaceae (p<0.01 and RR=3.23) and Staphylococcaceae (p<0.01 and RR=3.5) was associated to its increased incidence.CONCLUSIONS:Longitudinal study of microbioma profile allows early identification of patients at risk for major transplant-related complications such as sepsis by GN-MDR or acute GvHD, offering a new tool for individualized pre-emptive or therapeutical strategies to improve the outcome of allo-HSCT. DisclosuresCiceri:MolMed SpA: Consultancy.

Successful treatment with low‐dose gemtuzumab ozogamicin in combination chemotherapy followed by stem cell transplantation for children with refractory acute myeloid leukaemia

Successful treatment with low‐dose gemtuzumab ozogamicin in combination chemotherapy followed by stem cell transplantation for children with refractory acute myeloid leukaemia

Novel regulatory therapies for prevention of Graft-versus-host disease

Graft-versus-host disease is one of the major transplant-related complications in allogeneic hematopoietic stem cell transplantation. Continued efforts have been made to prevent the occurrence of severe graft-versus-host disease by eliminating or suppressing donor-derived effector T cells. Conventional immunosuppression does not adequately prevent graft-versus-host disease, especially in mismatched transplants. Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences. In this review, we discuss the role of dynamic immune regulation in controlling graft-versus-host disease, and how cell-based therapies are being developed using regulatory T cells and other tolerogenic cells for the prevention and treatment of graft-versus-host disease. In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed. Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease.

Clinical Applications for Biomarkers of Acute and Chronic Graft-versus-Host Disease

Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are serious complications of allogeneic hematopoietic cell transplantation. The complex pathophysiology of these disease processes is associated with immune system activation, the release of cytokines and chemokines, and alterations in cell populations. The blood levels of specific protein and cellular levels in patients with GVHD have correlated with the development, diagnosis, and prognosis of GVHD. Here, we review the most promising biomarkers for aGVHD and cGVHD with clinical relevance. The utility of GVHD biomarkers in clinical care of allogeneic hematopoietic cell transplantation recipients needs to be proven through clinical trials, and potential approaches to trial design are discussed.

Diarrhea during the Conditioning Regimen Is Correlated with the Occurrence of Severe Acute Graft-versus-Host Disease through Systemic Release of Inflammatory Cytokines

Graft-versus-host disease (GVHD) is a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although many indicators have been used to predict GVHD, the prediction of GVHD remains very difficult. Determining how to predict the occurrence of acute GVHD (aGVHD) as exactly as possible has been a huge challenge so far. Systemic release of inflammatory cytokines during the conditioning regimen and early-phase post-HSCT plays a crucial role in the generation of aGVHD; additionally, the conditioning regimen causes the damage to the intestinal tract. Diarrhea is a common symptom of intestinal tract damage during the conditioning regimen. We therefore performed a prospective study to investigate the relationship between diarrhea related to the conditioning regimen, systemic release of inflammatory cytokines during the conditioning regimen and the early-phase post-HSCT, and the development of aGVHD. This study demonstrated that duration of diarrhea was >5.5 days, with a maximal volume >8.72 mL/kg and a mean volume of diarrhea for days -3 to 0 >7.94 mL/kg were risk factors of grade II to IV aGVHD. Diarrhea with any 1 risk factor was defined as severe diarrhea. Furthermore, this study first confirmed that the correlation between diarrhea and aGVHD was related to the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 during the conditioning regimen and during the early phase after transplantation. Our study demonstrated that diarrhea related to the conditioning regimen could be used as a marker for the prediction of aGVHD and further explain the possible mechanism underlying the linkage described here. Therefore, for the patients with severe diarrhea related to the conditioning regimen, low-dose glucocorticoid may be used to reduce the levels of inflammatory cytokine release by a damaged intestinal tract, and possibly further reduce the occurrence of aGVHD. For these patients, prophylaxis of aGVHD may be need to be adjusted individually.

Change in serum proteome during allogeneic hematopoietic stem cell transplantation and clinical significance of serum C-reactive protein and haptoglobin

Successful hematopoietic stem cell transplantation (HSCT) involves the restoration of hematopoietic function after engraftment, arising from the differentiation and proliferation of hematopoietic stem cells. Several factors could influence the course of allogeneic-HSCT (allo-HSCT). Therefore, knowledge of serum proteome changes during the allo-HSCT period might increase the efficacy of diagnosis and disease prevention efforts. This study conducted proteomic analyses to find proteins that were significantly altered in response to allo-HSCT. Sera from five representative patients who underwent allo-HSCT were analyzed by 2-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry, and were measured on a weekly basis before and after allo-HSCT in additional 78 patients. Fourteen protein spots showing changes in expression were further examined, and most proteins were identified as acute phase proteins (APPs). Studies of 78 additional patients confirmed that C-reactive protein (CRP) and haptoglobin undergo expression changes during allo-HSCT and thus may have the potential to serve as representative markers of clinical events after allo-HSCT. Maximal CRP level affected the development of major transplant-related complications (MTCs) and other problems such as fever of unknown origin. Particularly, an increase in CRP level 21 days after allo-HSCT was found to be an independent risk factor for MTC. Maximal haptoglobin and haptoglobin level 14 days after allo-HSCT were predictive of relapses in underlying hematologic disease. Our results indicated that CRP and haptoglobin were significantly expressed during allo-HSCT, and suggest that their level can be monitored after allo-HSCT to assess the risks of early transplant-related complications and relapse.

Costs of Allogeneic Hematopoietic Stem Cell Transplantation

This study aims to determine the total costs after allogeneic hematopoietic stem cell transplantation (ASCT) and factors associated with increases or decreases in costs. We collected all in- and outpatient costs during 5 years in 93 patients who had undergone ASCT in 1998 and 1999 at our unit. The inpatient costs included all those related to a patient from the first day of admission until discharge and then all costs of readmission in the Stockholm area. The total median cost of five posttransplant years was 139,414 (52,095-345,640) euros (euros) or 167,296 US dollars (the rate of 1 euro is approximately 1.2 US dollars). The costs were highest during the first year-median inpatient and outpatient costs 100,650 euros and 13,066 euros, respectively. The total costs during the first year were higher in patients with acute graft-versus-host disease grades III-IV (relative hazards [RH] 1.35, P = 0.003), bacteremia (RH 1.33, P = 0.005), veno-occlusive disease of the liver (RH 1.32, P = 0.005), prophylaxis with granulocyte colony-stimulating factor (G-CSF; RH 1.31, P = 0.01), acute leukemia (RH 1.32, P = 0.008), and treatment in hospital instead of at home (RH 1.20, P < 0.07). During the early transplant period, a second transplantation (RH 1.28, P = 0.014) and hemorrhagic cystitis (HC; RH 1.24, P = 0.03) were also associated with higher costs. The total 5-year cost declined with longer survival rates (r = 0.4028, P < 0.001) and reduced intensity conditioning (RH 0.79, P=0.024). Higher costs of ASCT were associated with retransplantation, acute leukemia, G-CSF prophylaxis, hospital care, myeloablative conditioning, and major transplant-related complications.

Proinflammatory cytokines and their role in the development of major transplant-related complications in the early phase after allogeneic bone marrow transplantation.

Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha were frequently measured during the first 30 days after allogeneic bone marrow transplantation (BMT) in 84 consecutive adult patients. Major transplant-related complications (MTCs) occurred in 33% of cases and included veno-occlusive liver disease, idiopathic pneumonia syndrome, severe endothelial leakage syndrome and >grade II acute graft-versus-host disease. Compared with patients having minor complications, those with MTCs developed higher levels at times of maximal clinical signs (all cytokines, P<0.001), between days 0-5 post-BMT (IL-6 and IL-8, P<0.05) and days 6-10 (L-6, P<0.001; IL-8 and TNF, P<0.01) post-BMT. We could not discriminate patterns of cytokine release that were specific for any subtype of MTC. Higher levels of IL-8 during days 0-5 were associated (P=0.044) with early (<40 days) death. Multivariate analysis including patient and transplant characteristics as well as post-BMT levels of C-reactive protein showed that high average levels of one or more of the cytokines within the first 10 days post-BMT were independently associated with MTC (Odd's ratio: 2.3 [1.2-4.5], P=0.011). This study shows that systemic release of proinflammatory cytokines contributes to the development of MTC and provides a rationale for pre-emptive anti-inflammatory treatment in selected patients.

An early increase in serum levels of C-reactive protein is an independent risk factor for the occurrence of major complications and 100-day transplant-related mortality after allogeneic bone marrow transplantation.

We monitored levels of C-reactive protein (CRP) in 96 consecutive adult allogeneic BMT patients (age 15-50 years) transplanted in our unit. Major transplant-related complications (MTC) occurred in 32% of cases and included: hepatic veno-occlusive disease, pneumonitis, severe endothelial leakage syndrome and >II acute GVHD. Transplant-related mortality (TRM) before day 100 post-BMT was 13.5%. Variables included in a stepwise logistic regression model were: gender, age, disease category, donor type, T cell depletion, TBI, use of growth factors, bacteremia, mean CRP-levels >50 mg/l between days 0 and 5 (CRP day 0-5) and >100 mg/l between days 6 and 10 (CRP day 6-10) post-BMT. Only high CRP-levels (for MTC and TRM) (P < 0.001) and donor-type (for TRM) (P= 0.02) were independent risk factors. The estimated probability for MTC was 73% (CRP day 6-10 >100 mg/l) vs 17% (CRP day 6-10 <100 mg/l). Using the same cut-off levels, the probabilities for TRM were 36.5% vs 1% in the identical sibling donor situation and 88% vs 12.5% in other donor-type transplants. We conclude that the degree of systemic inflammation, as reflected by CRP-levels, during the first 5-10 days after BMT identifies patients at risk of MTC and TRM. Our data may be useful in selecting patients for clinical trials involving pre-emptive anti-inflammatory treatment.

Clinical Bone Marrow and Blood Stem Cell Transplantation

Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd edn. Edited by Kerry Atkinson. Cambridge University Press, 2000. Pp. 1500. £175.00. The second edition of this reference textbook represents an impressive coming together of world expertise in all aspects of haemopoietic stem cell therapy. The breadth of the book reflects an era when stem cell therapy is expanding in terms of the number of applicable diseases, availability of donors and safer delivery to older patients. Taking the pace of development into account, this text is as close as possible to being an exhaustive reference on the subject, from basic science to day-to-day management issues. The text is logically organized into several sections, each containing numerous chapters from recognized authorities. The sections include the historical and biological background of bone marrow transplantation, the global stem cell donor registry and practical procedures involved in preparing patients and donors, and in the manipulation of harvested cells. There are detailed clinical results of allogeneic and autologous procedures for all the presently considered therapeutic indications, both malignant and non-malignant. This includes newer considerations such as sickle cell disease, thalassaemia, solid tumours and autoimmune diseases. The second half of the book is dedicated to major transplant-related complications, which are usefully presented in an organ-specific format, including the psychosocial implications of undergoing a transplant procedure. This is followed by three sections covering recent developments pre, peri and post transplantation. One frequent criticism of large multiauthor texts, which of necessity take time to compile, is the omission of up-to-date information in rapidly developing areas. The three developments sections in this book attempt to overcome this criticism with detailed discussions and predictions for future ways forward. The pretransplant considerations include the role of minor histocompatibility antigens, non-myeloablative conditioning and the use of radiolabelled monoclonal antibodies and recombinant immunotoxins in preparative regimens. Immunological purging and new sources of stem cells and ex vivo expansion of stem cells are covered in the peri-transplant section, and the post-transplant section includes donor lymphocyte and dendritic cell therapy, new immune suppressive regimens for controlling graft-versus-host disease and suicide gene therapy. With over 1400 pages and 120 contributors, this text represents an all-encompassing aid to doctors, nurses and clinical scientists involved in stem cell transplantation and, as such, is to be highly recommended as a member of the transplant team!

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

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.

Monitoring of C-reactive protein after allogeneic bone marrow transplantation identifies patients at risk of severe transplant-related complications and mortality.

Patterns of C-reactive protein (CRP) release were derived from frequent CRP measurements in a cohort of 66 consecutive patients receiving allogeneic bone marrow transplants (BMT) in our unit. Based on a retrospective study of clinical events occurring within the first 40 days after BMT, patients with major transplant-related complications (MTC+ group, n = 22) could be separated from those with fever or mild complications only (MTC- group, n = 44). Treatment-related mortality in the MTC+ group was significantly higher: 32 vs 0% (P < 0.001). Major complications included veno-occlusive liver disease (VOD), severe endothelial leakage syndrome (ELS), pneumonitis and acute GVHD >II. The severity of complications was reflected by the patterns of CRP release with continuously high levels preceding the maximal signs and symptoms of MTC. Univariate analysis showed that, among other variables (sex, age, disease status at transplant, +/- TBI in the conditioning regimen, +/- use of myeloid growth factors after BMT, time to reach PN >200/mm3), three factors were significantly associated with MTC: maximal levels of CRP during the post-transplant episode (CRPmax) (296.6 +/- 91.8 vs 88.9 +/- 55.8 mg/100 ml, P < 0.001), the use of unmanipulated graft (no T depletion) (46.9 vs 12.5%, P < 0.009) and the CRP level on the day of BMT (CRPo) (42.7 +/- 55.4 vs 18.2 +/- 19.5, P = 0.045). In multivariate analysis, using a stepwise logistic regression model including the same variables, CRPmax appeared to be the strongest independent variable (P < 0.001) and a reliable (94% accuracy) parameter to assess the risk of MTC. Based on this model, CRP levels of 200 and 300 mg/100 ml are associated with a risk of 48 and 94% of developing MTC, respectively. We conclude that CRP monitoring after BMT identifies patients at risk of severe transplant-related complications and mortality.

Plasma cytokines in graft vs host disease and complications following bone marrow transplantation.

A cohort of 201 autologous or allogeneic bone marrow transplanted (BMT) patients were included for studying the evolution of circulating tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) by means of repeated plasma determinations. IL-6 levels were high during major transplant-related complications (TRC) or severe graft vs host disease (GVHD). High levels of TNF-alpha seemed to be associated with chronic GVHD but not with acute GVHD or TRC.

Complications of Lung Transplantation

This article summarizes the complications of lung transplantation. Complications discussed are categorized into (1) complications of the operation itself, including hemorrhage, the reimplantation response, airway anastomotic complications, cardiac and hemodynamic complications, and gastrointestinal complications; (2) complications of transplantation, including acute and chronic rejection; and (3) complications of the immunosuppressive agents used to prevent rejection, including infection, malignancy, and direct toxicities of the medications. This article describes the usual presenting features of these complications and summarizes strategies used by transplant providers for their prevention, early diagnosis, and treatment.