Obstructive lung disease after allogeneic bone marrow transplantation

We report the cases of 3 patients with marked dyspnea and an obstructive ventilation disorder associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation. This disorder was characterized by recurrent pulmonary infections and colonization of the lower respiratory tract by Pseudomonas aeruginosa. Two patients have shown rapidly progressive deterioration with death following due to respiratory failure. Intensive therapy with antibiotics, bronchodilators, high-dose steroids, and azathioprine was not effective in arresting the malignant course of this disorder.     

A boy with membranous nephropathy after allogeneic bone marrow transplantation

A 6-year-old boy developed bronchiolitis obliterans organizing pneumonia and nephrotic syndrome 5 months after allogeneic bone marrow transplantation from an unrelated donor for acute lymphoblastic leukemia. His renal biopsy showed membranous nephropathy. He was treated with prednisolone and cyclosporine A. Proteinuria disappeared 3 months after the onset of nephrotic syndrome. To our knowledge, this patient is the youngest case with nephrotic syndrome due to membranous nephropathy after hematopoietic stem cell transplantation.     

Adult bone marrow transplantation after stroke in adult rats

We transplanted adult whole bone marrow prelabeled with bromodeoxyuridine (BrdU) into the ischemic boundary zone of the adult rat brain at 1 day after 2 h of middle cerebral artery occlusion (MCAo). Approximately 3.3% of 10(6) transplanted bone marrow cells were BrdU reactive at 14 days after MCAo. BrdU-reactive cells expressed neuronal and astrocytic proteins, neuronal nuclei protein (NeuN, 1%), and glial fibrillary acidic protein (GFAP, 5%) immunoreactivities, respectively. In addition, bone marrow transplantation promoted proliferation of ependymal and subependymal cells, identified by nestin (a neuroepithelial stem cell marker), within the ventricular zone and subventricular zone (VZ/SVZ). These data suggest that intracerebral transplantation of bone marrow could potentially be used to induce plasticity in ischemic brain.     

Adult respiratory distress syndrome after renal transplantation: A case report

A potentially lethal case of "air-borne" adult respiratory distress syndrome, most likely consequent to cytomegalovirus (CMV) pneumonitis, is described in a kidney transplant patient. It was characterized by confluent densities on both lung fields with peripheral zones of normal radiographic pattern and with one of the highest values of extravascular lung water reported in the literature, in the presence of a normal pulmonary capillary wedge pressure. When specific conservative therapy for curing a potentially lethal CMV pneumonitis after kidney transplantation fails, we suggest that transplantectomy should be considered.     

Osteonecrosis of the femoral head after allogeneic bone marrow transplantation

A comparative retrospective analysis of 100 consecutive patients after bone marrow transplantation was performed with magnetic resonance imaging in addition to plain radiography for the development of osteonecrosis of the femoral head. The incidence and risk factors for osteonecrosis of the femoral head were identified, comparing various parameters concerning bone marrow transplantation between the groups with and without evidence of osteonecrosis. Nineteen (19%) of 100 patients had osteonecrosis of the femoral head develop. Four factors were found to be statistically significantly different between patients who had osteonecrosis develop and those who did not: younger age at the time of bone marrow transplantation, chronic graft-versus-host disease, cumulative dose of steroid, and intravenous pulse therapy with methylprednisolone. It was concluded that a low rate of complications and low dose steroid administration would reduce the incidence of osteonecrosis after bone marrow transplantation.     

Streptococcus pneumoniae mycotic aortic aneurysm after allogeneic bone marrow transplantation

BACKGROUND: Streptococcus pneumoniae (SP) is a common cause of community-acquired pneumonia and accounts for up to 30% of all cases of pneumonia. Patients with chronic graft-versus-host-disease (GvHD) after allogeneic bone marrow transplantation (BMT) have a high susceptibility to SP infections. So far, mycotic aneurysm resulting from SP has not been reported after BMT. METHODS: We report on a patient with extensive, chronic GvHD who developed low back pain 22 months after allogeneic BMT. RESULTS: Computed tomography of the abdomen displayed mycotic, saccular aneurysmatic enlargement of the infrarenal aorta, with leakage of contrast medium into the aneurysm. The aneurysm was resected, and the defect was closed with an autologous patch from the internal iliac artery. Bacteriologic samples from the abscess grew SP. The patient recovered uneventfully. CONCLUSIONS: This observation confirms the importance of pneumococcal prophylaxis after BMT and suggests that an aggressive diagnostic approach should always be considered in patients with chronic GvHD, even if they present with nonspecific symptoms.     

Repetitive DNA polymorphisms in following chimerism after allogeneic bone marrow transplantation

Information about the chimeric status of patients is of great importance in comparison of different conditioning and prophylactic regimens as well as for the post-bone marrow transplantation (BMT) therapies. In some cases, mixed chimerism (MC) can also be predictive of relapse. Analysis of the short tandem repeats (STR) loci by polymerase chain reaction (PCR) is a choice method for this purpose. In this study, we monitored 15 patients after BMT. Twelve of them underwent classical-conditioning regimen while the remaining three patients were subjected to non-myeloablative conditioning (minitransplantation). Evaluation of chimerism was performed using five STR and one variable number of tandem repeats (VNTR) locus. Four additional loci were PCR-amplified in cases of minitransplantation. Samples were analyzed by electrophoresis in an ALFexpress sequencer. MC was detected in seven cases of which it was predictive of relapse for two patients, who suffered from acute lymphocytic leukemia (ALL). The PCR-STR method proved to be a fast and relatively simple method, while the tested STR loci showed a high level of informativeness.     

Immune reconstitution after allogeneic bone marrow transplantation depleted of T cells

BACKGROUND: Immune reconstitution following transplantation in individuals who had received T-cell-depleted marrow from HLA identical siblings was serially documented and correlated with the clinical recovery. METHODS: Patients were preconditioned with radiation containing programs. GvHD prophylaxis was by T-cell depletion with CAMPATH 1G (ex vivo; median dose 20 mg). After transplantation lymphoid development was studied by flow cytometry and serum Ig concentrations were determined. Charts were reviewed to determine the effects of the immune reconstitution on the clinical performance. RESULTS: The mean donor mononuclear cell number infused was 0.89x10(8)/kg. Within 6 months all the patients recovered their blood parameters and only one required therapy for GvHD. However, despite normal blood counts, 15 suffered life-threatening opportunistic infections, developing at a median of 24 weeks post grafting, but occurring even after 11 months. At 8 weeks from marrow infusion when leukocyte values had normalized in 15/20, compared to normal, immunophenotyping of blood cells from BMT revealed a significantly reduced mean lymphocyte count (1.06, SD 0.83x10(9)/l; P = 0.01), cells expressing CD3 (0.7x10(9)/l, SD 0.68; P = 0.05), CD4 (0.13x10(9)/l, SD 0.21; P = 0.0001) and CD19 (0.04x10(9)/l, SD 0.05; P = 0.001). Populations expressing CD8 and CD56 remained within normal range throughout the study. Normalization of cell numbers displaying CD2, CD3 and CD19 was delayed until 52, 52 and 24 weeks respectively, while CD4 counts persisted subnormal even at 72 weeks. Serum IgA levels were significantly decreased for the entire study period. CONCLUSIONS: T-cell depletion with CAMPATH 1G while effectively preventing GvHD, also causes clinically significant and prolonged immunosuppression with apparently important clinical implications.     

Immune recovery following allogeneic bone marrow transplantation

A total of 144 evaluations of cell surface markers and cellular immune functions were carried out in 57 patients undergoing allogeneic bone marrow transplantation for acute leukemia in remission and relapse and for aplastic anemia. The periods tested were pretransplant, and 1-3, 4-6, 7-12 and more than 12 months posttransplant. The determination consisted of lymphocyte counts; lymphocyte surface marking using OKT3, OKT4, and OKT8 antibodies; and determination of adherent cells, lysozymes and antibody dependent cellular cytotoxicity (ADCC) against chicken red blood cells, human red blood cells, and CEM cells. Natural killer cells were determined against K562 target cells. Lymphoblastic responses were tested after stimulation with pokeweed mitogen (PWM), concanavalin-A (Con-A), and phytohemagglutinin (PHA). We found that the progression in the leukemic state (first remission, second remission, and relapse), prior to transplantation was paralleled by a decrease in T4 lymphocytes (976/microliter +/- 462; 411/microliter +/- 222; 372/microliter +/- 419; P = .04). There was a lack of helper cells and an inverted T4:T8 ratio beyond one year posttransplant independent of graft-versus-host disease status. Lymphocyte functions persisted to be depressed for more than one year. We found a direct correlation of T4 helper cells and an inverse correlation of T8 suppressor cells with lymphoblastic responses to mitogens. It is hoped that the longitudinal evaluations of immune functions after allogeneic bone marrow transplantation, and the characterization of the immune defects seen may lead to better immunorestorative treatments.     

Bone marrow repopulation capacity after transplantation of lymphocyte-depleted allogeneic bone marrow using counterflow centrifugation

Bone marrow from six allogeneic HLA-matched and MCL nonreactive siblings was fractionated by means of isopycnic flotation centrifugation and subsequent counterflow centrifugation. The low density fraction (d less than or equal to 1.070 g/ml) obtained by IFC contained 20% of the nucleated cells and more than 90% of the myeloid and erythroid progenitors. The putative stem cell fraction obtained by CC showed a satisfactory recovery (88%) of the CFU-GM and BFU-E and only 3.5% of the original number of T lymphocytes. Bone marrow repopulation capacity was not impaired in comparison with a comparable group of patients. Despite the average high age of this group (29.6 years), only one of the four evaluable patients developed graft-versus-host disease.     

Erythrocyte repopulation after allogeneic bone marrow transplantation. Analysis using erythrocyte antigens

Blood samples from 31 of 50 consecutive patients receiving bone marrow from an HLA-identical and mixed lymphocyte culture-nonreactive sibling were investigated for the presence of donor and autologous erythrocytes. Simple serological techniques using antigenic differences between donor and recipient and a blood transfusion policy taking these differences into account made this study possible. A total of 71% of the patients had donor erythrocytes demonstrable 4 weeks after bone marrow transplantation; almost all patients did so after 2 months. Disappearance or absence of donor red cells indicated poor patient prognosis. Persistence or reappearance of autologous erythrocytes in small percentages (0.05-10%) occurred without relapse of leukemia. Reappearance in high percentage (50-100%) indicated relapse.     

Regeneration of TdT+, pre-B, and B cells in bone marrow after allogeneic bone marrow transplantation

In 15 children transplanted with allogeneic bone marrow for acute leukemia and in complete remission, regeneration of the early stages of the B cell system was studied. Bone marrow aspirates taken before and longitudinally after BMT were investigated for pre-B and B cells by immunofluorescence techniques; in some cases, TdT+ cells were also determined. Normal values were derived from bone marrow samples taken from 23 healthy individuals who served as bone marrow donors. In normal bone marrow, B cells outnumber pre-B cells and the latter are more numerous than TdT+ cells. Before BMT, the numbers of BM pre-B were outside the normal range in all cases; B cell numbers were abnormal in most of the 11 patients studied, probably due to the antileukemic remission induction/consolidation therapy. After BMT, two distinct patterns of regeneration of the B cell system were observed. In 9 patients, TdT+ cells were considerably increased early after BMT. This was followed by a rise in pre-B cells, with values well above the normal range, and resulting in ratios of TdT+:pre-B cells and of pre-B cells:B cells that were transiently greater than 1. In the other 6 patients, the regeneration of TdT+ cells varied and the reconstitution of the pre-B cells was more gradual than in the first group, with pre-B-to-B cell ratios less than 1 during the whole observation period. The only consistent difference between the patients of the two groups, possibly relevant to the regeneration of the B cell lineage, was the duration of corticosteroid therapy, which was much longer in the 6 patients with slow-pace reconstitution. The pace of regeneration of the B cell system in the bone marrow was correlated with the recovery of the humoral immunity, as indicated by a significant increase in specific antibody titers after the second vaccination with diphtheria-tetanus-poliomyelitis vaccine in 7 of 9 patients in the rapid-pace group, versus 2 of 6 patients in the slow-pace group.     

Gamma-interferon production capacity and T lymphocyte subpopulation after allogeneic bone marrow transplantation

T cell phenotypes after bone marrow transplantation (BMT) were investigated using monoclonal antibodies (moAbs) reactive to lymphocyte cell surface antigens. Patients' T cells showed decreased percentages of OKT4, 4A and 9.3-positive T cells, and increased percentages of OKT8, human Ia, and Leu-7-positive T cells. These changes in T cell phenotype persisted for a long period after BMT and had no correlation with the occurrence of graft-versus-host disease (GVHD). No lymphocyte activation antigens such as TIA (Tac) or transferrin receptor (5E9) were detected after BMT. The capacity of the patients' lymphocytes to produce gamma-interferon (IFN-gamma) was measured after incubation of lymphocytes with mitogen. Patients' lymphocytes produced significantly lower levels of IFN-gamma than the normal controls. This failure of IFN-gamma production showed no correlation with stimulation index of mitogen blastogenesis or changes of T cell population. Thus, not only T cell phenotype but also measurement of IFN-gamma production of lymphocyte may be useful in detecting immunological abnormalities in patients who receive BMT.     

Pulmonary hypertension associated with pulmonary occlusive vasculopathy after allogeneic bone marrow transplantation

BACKGROUND: Pulmonary vasculature abnormalities, including pulmonary veno-occlusive disease, have been demonstrated in marrow allograft recipients. However, it is often difficult to make a correct diagnosis of pulmonary lesions. METHODS: An open lung biopsy was performed on a patient who developed severe pulmonary hypertension after bone marrow transplantation for T-cell lymphoma. RESULTS: An open lung biopsy specimen demonstrated pulmonary arterial occlusion due to intimal fibrosis and veno-occlusion. The most striking alteration was partial to complete occlusion of the small arteries by fibrous proliferation of the intima. CONCLUSION: High-dose preparative chemotherapy and radiation before transplantation are thought to have contributed to the development of vasculopathy in this patient, because arterial occlusion by intimal fibrosis and atypical veno-occlusion are often associated with lung injury due to chemoradiation. An open lung biopsy is essential for diagnosing pulmonary vascular disease presenting signs compatible with posttransplantation pulmonary hypertension.