Pneumocystis carinii pneumonitis following bone marrow transplantation.

Pneumocystis carinii pneumonitis (PCP) can occur in immunocompromised hosts, especially AIDS and cancer patients. Although recent research has focused on PCP in AIDS patients, few studies have described the clinical presentation of PCP in recipients of bone marrow transplantation (BMT). Between 1976 and 1991, of 1454 BMT patients at the University of Minnesota, PCP was documented in only 19. Eighteen of these had not been receiving PCP prophylaxis. Patients presented with a brief period (2-10 days) of symptoms including dyspnea, cough, and fever in greater than 75% of patients, but had only scant abnormal physical findings. Chest X-rays showed bilateral infiltrates in 58% of all patients, though 15% had no or minimal X-ray findings. Bronchoscopic alveolar lavage confirmed the diagnosis most often, but 13% of lavages were negative and required biopsy for the diagnosis. High dose trimethoprim-sulfamethoxazole was the initial treatment for 84% of the patients though 25% of these patients were later switched to pentamidine due to poor response or hypersensitivity reactions. Despite prompt diagnosis and therapy, overall survival was poor, with only 37% of patients surviving pneumonitis. Patients developing PCP less than 6 months post-BMT had greater mortality (89%) versus only 40% in later onset PCP (p less than 0.0001). Despite this better survival in the late-onset PCP cohort, the development of pneumonitis in these patients underscores the necessity for continued PCP prophylaxis beyond 1 year in some patients. Ongoing immunocompromise and need for prophylaxis should be appreciated in patients with graft-versus-host disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Granulomatous pneumonitis following bone marrow transplantation

We describe the rare occurrence of a granulomatous pneumonitis seen in a patient following allogeneic bone marrow transplantation. Interestingly sarcoidosis was diagnosed in the marrow donor less than a year after donating his bone marrow.     

Lymphocytic pneumonitis following bone marrow transplantation in severe combined immunodeficiency

Lung disease in patients with severe combined immune deficiency (SCID) undergoing bone marrow transplantation (BMT) is most commonly caused by infection. Noninfectious episodes of pulmonary disease following BMT are more frequently encountered in patients with hematologic disorders or malignancy and are probably related to ablation therapy or graft-versus-host disease (GVHD). In contrast, patients with SCID do not receive chemotherapy before an HLA-identical allogeneic BMT and they do not suffer significant GVHD. We report a patient who developed severe lung disease during the period of rapid engraftment following an HLA-identical allogeneic bone marrow transplantation. Lung biopsy showed dense lymphocytic infiltrates in the alveolar septae and no evidence of infection. Following the idea that the acute recruitment of engrafted lymphocytes may have contributed to or caused the pulmonary disease, we have attempted to suppress cellular immunity by administering high-dose methylprednisolone. The patient's lung disease rapidly improved and eventually completely resolved.     

异基因骨髓移植新策略:骨髓腔内骨髓移植

骨髓移植逐渐成为治疗造血障碍疾病、先天性免疫缺陷疾病、自身免疫性疾病的重要治疗方法。异基因骨髓细胞的植入可以诱导抗原匹配器官的免疫耐受。临床上广泛地把骨髓移植作为一种诱导免疫耐受的方法,但由于预处理的毒性、移植物抗宿主病(GVHD)、植入失败带来的高发病率和死亡     

Hemostatic abnormalities and changes following bone marrow transplantation.

Hemostatic parameters were examined in 39 patients who underwent allogeneic bone marrow transplantation (BMT). Twenty-six patients survived and 13 patients died within 6 months after BMT. The main causes of death were acute graft-versus-host disease (GVHD: n=6), veno-occlusive disease (VOD: n=2), and thrombotic microangiopathy (TMA: n=2). Plasma levels of D-dimer and thrombomodulin (TM) were significantly elevated in the non-survivor group. Plasma levels of soluble fibrin (SF) and Fas were significantly elevated in the non-survivor group at 1 to 4 weeks after BMT. Plasma levels of thrombin-antithrombin complex (TAT), D-dimer, and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPA-PAI-1 complex) were significantly elevated in patients with complications after BMT. Plasma levels of TAT, D-dimer, and tPA-PAI-1 complex were significantly elevated in patients with GVHD. These results suggest that abnormalities of hemostatic parameters might predict poor outcomes or complications in patients with BMT.     

Immunophenotypic and ultrastructural study in peripheral blood neutrophil granulocytes following bone marrow transplantation

Neutrophil studies after bone marrow transplantation (BMT) describe chemotactic and phagocytotic alterations and dyshaemopoiesis. Neutrophil granulocytes (NG) in peripheral blood after BMT were analysed in 28 patients. 14 patients (six receiving GM-CSF) underwent autologous BMT and 14 underwent allogeneic BMT. Immunophenotypic and electron microscopic studies were performed during post-BMT granulopoietic regeneration. Results were compared with NG from 15 healthy bone marrow donors (control group A) and from six patients receiving intensive chemotherapy before autologous BMT (control group B).
A significant increase in CD15 and a decrease in 8C7 antigen expression was observed in peripheral blood NG from BMT patients compared with controls A. MPO-7 in NG after BMT did not differ from control group A. Autologous BMT patients showed a lower percentage of NG expressing 13F6, 31D8 and CD16 (Leu 11a) than allogeneic BMT patients, and a significant decrease in 8C7 antigen expression compared with patients receiving intensive chemotherapy. Ultrastructurally, a marked decrease of azurophilic granules was observed in NG from BMT patients compared with control groups A and B. These data indicate that repopulation after BMT was made by phenotypically less mature NG with dysgranulopoietic features. Differences between autologous and allogeneic BMT patients may be partly related to GM-CSF usage. In conclusion, NG present immunophenotypic and ultrastructural changes after BMT which may be involved in abnormal NG response against bacterial infections, although further investigation is needed.     

Regeneration of peripheral blood cells following allogeneic bone marrow transplantation for severe aplastic anaemia

S ummary . We have studied the pattern of regeneration of peripheral blood cells following ABO compatible bone marrow transplantation for severe aplastic anaemia. 18 patients were treated with cyclosporin A and six with methotrexate for post graft immunosuppression. The number of days taken for the neutrophil count to reach 0.5 × 10⁹/l, the lymphocyte count to reach 1.0 x 10⁹/l, the platelet count to reach 100 × 10⁹/l and the reticulocytes to reach 1% was shorter in the CyA treated patients. This finding reached statistical significance for all types of cells except the platelets (neutrophils, P < 0.001; lymphocytes, P < 0.02; platelets, P > 0.05; reticulocytes, P < 0.001).     

Cortical blindness and seizures in a patient receiving FK506 after bone marrow transplantation.

A 54-year-old woman with a myelodysplastic syndrome treated with high-dose chemotherapy and an allogenic bone marrow transplant developed acute cortical blindness while receiving tacrolimus (FK506). MRI showed white matter abnormalities. After discontinuation of FK506, the patient's vision returned within 8 days. FK506 neurotoxicity is similar to cyclosporine neurotoxicity and can occur in allogenic bone marrow transplant patients treated with FK506.     

Adoptive immunotherapy with haploidentical allogeneic peripheral blood lymphocytes following autologous bone marrow transplantation

Patients who undergo autologous bone marrow transplantation for acute leukemia are at high risk for relapse. We have evaluated the feasibility of administering cell-mediated immunotherapy with family-related haploidentical lymphocytes following autologous bone marrow transplantation in order to evoke a graft-vs-leukemia effect in the autologous setting.Twenty-six patients aged 1.5-48 years were enrolled in this study. Eighteen suffered from acute myeloid leukemia, seven from acute lymphoblastic leukemia, and one from myelodysplastic syndrome. Eleven patients were transplanted in first remission, six in second remission, one in fourth remission, and eight in relapse. Conditioning consisted of Busulfan/Cyclophosphamide or Busulfan/Thiotepa/Cyclophosphamide. Nineteen patients (Group A) were treated with gradual increments of haploidentical donor T cells, starting on day +1, with an additional course of T cells plus intravenous recombinant human interleukin-2 one month later if no signs of graft-vs-host disease developed in the interim. Seven patients (Group B) were treated with high-dose haploidentical T cells on day +1 in conjunction with intravenous recombinant human interleukin-2.Donor cells were detected in the peripheral blood of both groups 12-48 hours post-cell-mediated immunotherapy, peaking at 48 hours. Three patients in Group A developed transient Grade I graft-vs-host disease. One patient in Group B developed Grade I, and three Grade IV, graft-vs-host disease. Group A patients engrafted normally, but the Group B patients with Grade IV graft-vs-host disease showed no signs of engraftment.Our results show that it is feasible to induce graft-vs-host disease in the autologous stem cell transplantation setting. However, the high-dose regimen of haploidentical T cells in conjunction with interleukin-2 results in severe toxicity and nonengraftment.     

CMV monitoring after peripheral blood stem cell and bone marrow transplantation by pp65 antigen and quantitative PCR.

We prospectively monitored 74 consecutive allogeneic and 50 autologous patients after bone marrow/stem cell transplantation from May 1999 to October 2000 at our institution with quantitative CMV PCR and pp65 antigen assay once weekly from conditioning therapy to days 120 and 80 after transplantation, respectively. Written informed consent was obtained from every patient. CMV prophylaxis consisted of acyclovir during transplant. Additionally all patients received only platelet products from CMV-negative donors. In the case of CMV infection preemptive therapy with gancyclovir was applied. In the case of CMV disease high-dose immunoglobulin was given as well. In the allogeneic setting 16 out of 74 (22%) patients developed a positive PCR. Seven episodes of a positive pp65 antigen assay occurred in six allograft recipients. In the autologous setting no positive assay was found during the whole observation period. Additionally, in 6/16 patients a lymphoproliferative assay was performed during CMV infection. Two patients showed a positive (15 and 5.4) and four a negative (2,1.6,1,1.8) stimulation index.     

Rapid onset retinopathy in a diabetic patient following bone marrow transplantation

We report a 38-year-old man who presented in 1998 with advanced multiple myeloma and newly diagnosed diabetes mellitus (DM). Subsequent BMT has been successful after conditioning with melphalan and total body irradiation, but significant ischaemic retinopathy has developed. Chemotherapeutic agents, total body irradiation, and DM are likely to have been co-factors in precipitating the rapid onset of retinopathy. Routine ophthalmic surveillance is recommended for all patients after BMT, particularly for those with additional risk factors for the development of retinopathy such as DM.     

Early treatment of CMV antigenemia with ganciclovir for prevention of fatal CMV disease in patients receiving marrow from HLA-matched unrelated donors.

The effect of early treatment of cytomegalovirus (CMV) antigenemia with ganciclovir (DHPG) for the prevention of CMV disease was evaluated in 25 patients with hematological malignancy who had received marrow from human leukocyte antigen-matched unrelated donors at our institution. CMV antigenemia occurred in 17 of 25 patients, a high rate of 68%, and was initially detected between 4 and 8 weeks after bone marrow transplantation (BMT) (median time 5 weeks). The incidence of CMV antigenemia was statistically higher in those patients given steroids or antithymocyte globulin (P < 0.01). All 17 CMV antigenemia-positive patients were treated with DHPG until antigenemia was cleared, and this treatment was resumed if antigenemia occurred. CMV antigenemia eventually became negative in all cases. One major drawback of DHPG was that leukopenia was observed in six patients (35%). CMV disease occurred in six patients despite early treatment of CMV antigenemia with DHPG (24%, 6 of 25 patients). Four of them developed CMV disease in the early phase (within six months) and two in the late phase (more than six months). All CMV diseases in the early phase were easily cured by treatment with DHPG while monitoring CMV antigenemia, but CMV disease in the late phase did not respond to DHPG and led to the death of one patient. On the other hand, there were no patients who developed CMV disease in the antigenemia-negative group. Thus, although early treatment using our method was effective in clearing CMV antigenemia in unrelated BMT, it did not totally prevent CMV disease. A further method of early treatment for the prevention of fatal CMV disease is required.     

Longitudinal changes in pulmonary function following bone marrow transplantation

We prospectively followed a well characterized cohort of patients post-bone marrow transplantation for changes in pulmonary function. Thirty-four recipients without respiratory symptoms were available for follow up with a mean of two years. Spirometry and other measures of lung volume were well preserved following bone marrow transplantation. A progressive 11.9 percent decline in percent predicted diffusing capacity per year occurred. Age, cigarette smoking, type of cytoreductive therapy, type of GVHD prophylaxis, and the occurrence of AGVHD did not affect longitudinal changes in pulmonary function. Patients receiving transplants for CML developed a highly significant fall in diffusing capacity. Asymptomatic patients with CGVHD developed evidence of progressive obstructive ventilatory impairment. This suggests a subclinical spectrum of patients who may progress to the development of bronchiolitis obliterans and respiratory failure post-bone marrow transplantation.     

Association of cytomegalovirus interstitial pneumonitis with HLA-type following allogeneic bone marrow transplantation

Certain human leukocyte antigens may increase the risk of cytomegalovirus interstitial pneumonitis, an important complication of bone marrow transplantation. The prevalence of this pneumonitis was compared between patients possessing either HLA-B51 or HLA-B52 and patients without either antigen. The role of tumor necrosis factor-alpha in cytomegalovirus interstitial pneumonitis was also studied. Among 72 patients undergoing allogeneic bone marrow transplantation at our institution during the past 5 years, HLA-B51 or -B52 was detected in 29. Among these 29 patients, 13 (45%) developed cytomegalovirus interstitial pneumonitis, a significantly higher rate (P < 0.001) than among patients without these HLA types (4/43, 9%). In the pre-conditioning and stable phases, tumor necrosis factor-alpha levels were higher in patients with HLA-B51 or HLA-B52 than in patients without (P < 0.05; t-test). Throughout the period from pre-conditioning to around day 40, except on day 0, tumor necrosis factor-alpha levels were also significantly higher (P < 0.05 to P < 0.001) in patients developing cytomegalovirus infection than in those without it. These results suggest that HLA-B51 and HLA-B52 may be risk factors for cytomegalovirus interstitial pneumonitis after bone marrow transplantation, with an increase of tumor necrosis factor-alpha also being involved.     

Interstitial pneumonitis in T cell-depleted bone marrow transplantation

The incidence of interstitial pneumonitis (IP) was reviewed in 80 consecutive patients who received allogeneic T lymphocyte-depleted bone marrow transplantation (BMT) for malignant and non-malignant diseases. Pretransplant conditioning used in malignant disorders included total lymphoid irradiation (TLI) 150 cGy x 4, total body irradiation (TBI) 200 cGy x 6, and cyclophosphamide (CY) 120 mg/kg. In non-malignant diseases conditioning included no TBI, but adjusted doses of TLI in addition to CY (severe aplastic anemia) or CY and busulfan (severe beta-thalassemia major). In the malignant group only one patient developed graft-versus-host disease (GVHD) grade I; IP developed in 12 out of 61 patients (19.7%) and IP-associated fatality occurred in five patients (8.2%). Cytomegalovirus (CMV) was associated with only two of the five fatal IP. In the non-malignant group there was no GVHD; one patient out of 19 (5.2%) had IP, which was fatal and not associated with CMV. These data indicate that fatal IP may appear in the absence of GVHD. The relatively low incidence of IP-related mortality in recipients of allogeneic T lymphocyte-depleted BMT suggests that although prevention of GVHD and elimination of drugs used for GVHD prevention may reduce the incidence of fatal pulmonary complications, other approaches have to be investigated for complete prevention of IP which still represents a major complication in patients with malignant hematologic disorders treated by allogeneic BMT.     

Chimerism monitoring by VNTRs polymorphism analysis in a patient who received allogenic bone marrow transplantation]

A 39-year-old female diagnosed as acute myelogenous leukemia received allogenic bone marrow transplantation (BMT) pre-conditioned with busulfan and cyclophosphamide regimen from her HLA identical sibling. To distinguish donor and recipient cells, we analyzed variable numbers of tandem repeats (VNTRs) polymorphisms using a YNH-24 probe by Southern blot hybridization. VNTRs polymorphism analysis documented the engraftment of donor cells, relapse of recipient cells, and mixed hematopoietic chimerism. Assessment of the chimerism state is important for determining the prognosis of patients undergoing BMT, and VNTRs polymorphisms analysis is very useful for identifying the chimerism state.     

Regeneration of peripheral blood cells following ABO incompatible allogeneic bone marrow transplantation for severe aplastic anaemia

The regeneration of peripheral blood cells in six patients receiving ABO incompatible bone marrow transplants for severe aplastic anaemia has been studied. The results are compared with those of 18 similar aplastic patients treated with ABO compatible transplants. Reticulocyte recovery in the ABO incompatible cases was significantly delayed (P less than 0.01) and associated with greatly prolonged red cell transfusion requirements (P less than 0.001). Peripheral blood regeneration of neutrophils, lymphocytes and platelets was also significantly delayed (P less than 0.01). Platelet support was required for longer in the ABO incompatible cases (P less than 0.001) but there was no increase in the incidence or severity of infections in the post transplant period.