Reimmunization after allogeneic bone marrow transplantation

BACKGROUND/AIMS: Patients with cirrhosis and ascites show high plasma concentrations of endothelin. The aim of the current study was to investigate whether this feature is a compensatory response to effective hypovolemia or a consequence of systemic endotoxemia. METHODS: Protocols 1 and 2 assess the effect of acute changes in effective blood volume on plasma endothelin, and protocol 3 investigates the relationship between plasma endotoxin and endothelin in patients with cirrhosis and ascites. Protocol 1 included nine healthy subjects and 26 patients with cirrhosis studied during supine rest, upright tilt (which decreases effective blood volume) and cycloergometric exercise (which activates vasoactive systems by a baroreceptor independent mechanism). Protocol 2 included six patients studied before and 1 and 3 h after the intravenous administration of a plasma expander. In protocol 3, the plasma levels of endothelin and endotoxin were measured in 17 non-infected patients with cirrhosis and also in four patients with spontaneous bacterial peritonitis at diagnosis and following resolution of infection. RESULTS: Plasma endothelin was 3-5 times higher in patients with cirrhosis than in healthy volunteers. In healthy subjects, upright tilt and exercise were associated with a significant activation of the renin-aldosterone and sympathetic nervous systems and an increase in plasma endothelin. In patients with cirrhosis, upright tilt and exercise were associated with a significant increase and plasma volume expansion with a marked suppression of the renin-aldosterone and sympathetic nervous systems. However, in these patients none of these maneuvers affected plasma endothelin levels. In the patients with cirrhosis in protocol 3, there was no correlation between plasma endotoxin and endothelin. Resolution of peritonitis was associated with a marked fall in plasma endotoxin and no changes in plasma endothelin. CONCLUSIONS: These findings suggest that mechanisms other than effective hypovolemia or systemic endotoxemia are involved in the increased plasma endothelin of cirrhosis with ascites.     

Augmented proliferation of human alveolar macrophages after allogeneic bone marrow transplantation

After allogeneic bone marrow transplantation (allo-BMT), recipient alveolar macrophages (AM) are gradually replaced by AM of the donor origin. An influx of mononuclear phagocytes of donor origin to the lung is responsible for the repopulation, but the detailed kinetics remain unclear. We therefore studied 24 BMT recipients who underwent bronchoalveolar lavage (BAL) from 24 to 83 days after BMT. AM cell number, size, morphology, proliferating ability, and genotype of AM were measured. Before day 50, the number and size of AM in BAL fluid were similar to those of normal nonsmokers. However, after day 50, the mean number of AM increased threefold and the mean cell size decreased due to the increase of small AM. These small cells are presumably of donor origin based on DNA fingerprinting analysis and based on fluorescence in situ hybridization for the Y chromosome in a sex-mismatched case. Immunohistochemistry and cell cycle analysis demonstrated that the increase in AM number coincided with a remarkable increase of AM expressing proliferating cell nuclear antigen, suggesting that small AM are proliferating. This is the first report representing that augmented proliferation of donor AM in situ may contribute to the reconstitution of AM population after BMT.     

Cyclosporine-related encephalopathy following allogeneic bone marrow transplantation

Idiopathic granulomatous hepatitis is a rare disease of unknown cause that is characterized by recurrent fevers and granuloma in the liver. Attempts to define an exact etiology of the fever of granulomatous hepatitis frequently do not yield a precise diagnosis. Idiopathic granulomatous hepatitis was confirmed after a thorough work up and negative cultures and serologies were obtained, and in the absence of another condition that could lead to granulomas in the liver. We have experienced a 67-year-old female patient who presented with prolonged fever for 2 months and revealed granuloma in liver biopsy. She was treated with glucocorticosteroid and defervescence resulted.     

Cytokine messenger RNA expression by donor-specific cytotoxic T-cell clones after allogeneic heart transplantation

BACKGROUND: Aspergillosis is an uncommon yet serious opportunistic infection in patients with AIDS. It has been extensively reported in HIV-infected adult patients. To our knowledge there are no studies that describe the epidemiology, clinical manifestations and outcome of aspergillosis in a large HIV-infected pediatric population. METHODS: We reviewed the records of all 473 HIV-infected children followed in the Pediatric Branch of the National Cancer Institute for 9 years from 1987 through 1995 for the presence of Aspergillus infection. RESULTS: Seven (1.5%) patients developed invasive aspergillosis during the study period. All patients had low CD4 counts reflecting severe immunosuppression. Sustained neutropenia (> 7 days) or corticosteroid therapy as a predisposing factor for invasive aspergillosis was encountered in only two patients (28%). Invasive pulmonary aspergillosis developed in five patients and cutaneous aspergillosis in two. The most common presenting features in patients with pulmonary aspergillosis were fever, cough and dyspnea. Patients with cutaneous aspergillosis were diagnosed during life and successfully treated with amphotericin B and surgery, whereas diagnosis of pulmonary aspergillosis was made clinically in only one patient. CONCLUSIONS: Aspergillosis is an uncommon but highly lethal opportunistic infection in HIV-infected children. Invasive pulmonary aspergillosis should be considered in the differential diagnosis in febrile, HIV-infected children with persistent pulmonary infiltrates.     

Intermediate TCR cells can induce graft-versus-host disease after allogeneic bone marrow transplantation

In this study we compared memory performances of 29 probable patients with AD (17 mildly and 12 moderately demented) with those of 39 healthy young subjects, 36 elderly subjects (matched with the AD group for age and years of schooling), and 19 healthy very old subjects. In most of the memory tasks used in the present study, a progressive decline in performance was observed passing from the Young to the Elderly to the Very Old to the AD group. However, patients with AD were selectively impaired in the backward reproduction of verbal and spatial span sequences and in the semantic encoding of verbal material. These data are consistent with the hypothesis of not only quantitative but also a qualitative discontinuity between the process of normal aging and the dementia syndrome.     

Late pulmonary impairment following allogeneic bone marrow transplantation

The pulmonary function of 88 consecutive leukemic patients who had undergone allogeneic bone marrow transplantation (BMT) was studied beforehand, at 3 months, at 6 months, and annually thereafter until 5 years after grafting. The parameters for function which are indicative for obstructive and restrictive lung disease deteriorated in all patient groups during the first 3 to 6 months after BMT but partially recovered within one year. Long-term decline in lung function was similar in all patient groups, and neither the onset nor the magnitude of pulmonary dysfunction was related to the occurrence of pulmonary impairment within 6 months after grafting. Multivariate analysis was then employed to assess predictors for long-term pulmonary disease. Despite the obvious effect of chronic graft versus host disease on the course of lung function, it was in itself not a significant predictor of long-term pulmonary outcome. Rather, the conditioning regimen turned out to be indicative; compared with busulfan, fractionated total body irradiation was demonstrated to be clearly superior with a lower incidence of both restrictive and obstructive long-term lung impairment. Our data indicate a previously unknown long-term side effect of busulfan conditioning.     

Phimosis as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation

Chronic GVHD is one of the major complications of BMT, involving a variety of organs, but rarely involving the genitourinary system. We report a patient who simultaneously developed extensive chronic GVHD and phimosis after BMT. From the clinical course and pathological findings, chronic GVHD was considered to be responsible for the phimosis. Despite intensive immunosuppressive therapy, the phimosis persisted. Phimosis is a rare complication after BMT, which may often remain neglected. Possibility of this complication should be considered in patients with chronic GVHD.     

Oral health of children undergoing allogeneic bone marrow transplantation

BACKGROUND: Mixed bone marrow chimerism reliably produces donor-specific transplantation tolerance for a variety of solid organ and cellular grafts. We used a rat heterotopic tracheal transplant model for chronic rejection to investigate whether mixed chimerism could successfully prevent obstructive airway disease. METHODS: Mixed allogeneic chimeras were prepared by reconstituting lethally irradiated Wistar-Furth (WF) recipients with a mixture of 5 x 10(6) T-cell-depleted syngeneic (WF) and 100 x 10(6) T-cell-depleted allogeneic (ACI) bone marrow cells (ACI + WF --> WF). Mixed chimerism was present in all animals 28 days after bone marrow transplantation. Donor-specific, syngeneic, or major histocompatibility complex (MHC)-disparate allogeneic tracheas were implanted in recipient's omentum and removed for histologic analysis 30 to 150 days after transplantation. RESULTS: At 30 days after implantation, median luminal obstruction grades (0=none, 4=complete) of syngeneic and allogeneic tracheas were 0 and 4, respectively. Donor-specific (ACI) tracheas implanted in chimeric (ACI + WF --> WF) recipients were remarkably free of obstruction (median luminal obstruction grade=0 at 150 days) and had excellent preservation of respiratory epithelium. Third-party F344 tracheas implanted in chimeric recipients developed progressive luminal obstruction (grade 2 at 30 days, grade 3 at 90 days). CONCLUSIONS: Mixed allogeneic chimerism induces donor-specific tolerance and prevents development of the characteristic fibroproliferative obstructive lesion of bronchiolitis obliterans in a rat heterotopic tracheal transplant model. Excellent preservation of tracheal structure and morphology was achieved across major and minor histocompatibility barriers.     

Possible transmission of sarcoidosis via allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) was performed in a 34-year-old man for non-Hodgkin's lymphoma. Two years before bone marrow harvest, pulmonary sarcoidosis was diagnosed in the donor. After steroid therapy, disease of the donor was in clinical remission with only minor radiological signs at the time of BMT. On day 90 after BMT, active sarcoidosis was diagnosed in the recipient. Besides radiologic signs and increased angiotensin converting enzyme levels, diagnosis was proved by characteristic histologic changes in lung and liver biopsies. Immunosuppressive therapy was changed from high dose cyclosporine to high dose methylprednisolone and symptoms promptly resolved within 10 weeks. This case indicates the possibility of transmission of sarcoidosis by marrow transplantation.     

Diffuse alveolar hemorrhage associated with idiopathic interstitial pneumonia syndrome after allogeneic bone marrow transplantation

Atherosclerosis may represent a significant cause of death and morbidity in patients with systemic lupus erythematosus. Coronary involvement is more premature in lupus patients. We present the case of a young woman diagnosed with SLE at the age of 20 years who had a myocardial infarction at age 29 years. We review the mechanisms of atherosclerosis, the interrelations between atherosclerosis and autoimmunity, and between atherosclerosis and SLE. We also review the risk factors, influence of disease and treatment and the guidelines for management of accelerated atherosclerosis in lupus patients.     

Long-term follow-up of immunosuppressive treatment for obstructive airways disease after allogeneic bone marrow transplantation

BACKGROUND: Locally advanced thyroid cancer invading the tracheal cartilage represents a difficult treatment dilemma during thyroidectomy. METHODS: A retrospective chart review was performed to determine the results of laryngotracheal resection or tracheal cartilage shave with adjuvant radiotherapy in patients with locally advanced thyroid cancer invading the upper airway. RESULTS: Of 597 patients undergoing thyroidectomy for thyroid cancer, 40 were found to have laryngotracheal invasion. Thirty-five patients with superficial invasion underwent cartilage shave procedures with adjuvant radiotherapy; five with full-thickness invasion underwent radical resection, including tracheal sleeve resection (n = 3) or total laryngectomy (n = 2). Histologic subtypes included papillary (n = 32), follicular (n = 2), Hurthle cell (n = 1), medullary (n = 3), and anaplastic (n = 2). Of the cartilage shave group, 25 are currently alive with no evidence of disease at a mean follow-up of 81 months (range 1-290). Six developed isolated local/regional recurrence and were managed with total laryngectomy (n = 1), tracheal resection (n = 1), cervical lymphadenectomy (n = 1), or repeat radiotherapy (n = 3). All six patients remain free of disease at a mean follow-up of 5 years. Of those who underwent initial laryngotracheal resection, four remain free of disease at a mean follow-up of 5 years. The rates of 10-year disease-free survival and overall survival for all patients were 47.9% (95% confidence interval [CI] 24.8, 71.0) and 83.9% (95% CI 70.3, 97.5), respectively. CONCLUSIONS: These data suggest that adequate management of thyroid cancer with laryngotracheal invasion can be achieved with a more conservative surgical approach and adjuvant radiotherapy, reserving more radical resections for extensive primary lesions or locally recurrent disease.     

Lamivudine treatment for chronic replicative hepatitis B virus infection after allogeneic bone marrow transplantation

The risk of severe hepatic damage in patients with chronic hepatitis B virus (HBV) infection is well known; more effective treatments for this infection are needed. Lamivudine is being studied in immunocompetent and immunosuppressed HBV infected patients. We report a patient suffering from chronic replicative HBV infection after allogeneic BMT, who responded to lamivudine therapy. A 24-year-old woman with CML received an allogeneic BMT from her HLA-identical sister in June 1992. Before transplant, her HBV status demonstrated viral contact without active infection (HBsAb+, HBcAb+ IgG, HBeAb+). Four months after BMT mild chronic liver GVHD appeared, requiring immunosuppressive treatment. Antibodies to HBV completely disappeared post-transplant. Acute icteric hepatitis occurred 2 years later, with HBsAg+, high level of HBV-DNA, HBeAg+ and HBcAb IgM+. Lamivudine 100 mg/day rapidly reduced transaminase levels and effected HBV-DNA disappearance within 2 months. The treatment was well tolerated; no hematological side-effects occurred. This preliminary observation warrants further investigation of lamivudine treatment in bone marrow transplanted patients with active HBV infection.     

Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation

The long-term biochemical and clinical effectiveness of allogenic bone marrow transplantation (BMT) was shown in a severely affected, transfusion-dependent 18-month-old female with congenital erythropoietic porphyria (CEP), an autosomal recessive inborn error of heme biosynthesis resulting from mutations in the uroporphyrinogen III synthase (URO-synthase) gene. Three years post-BMT, the recipient had normal hemoglobin, markedly reduced urinary porphyrin excretion, and no cutaneous lesions with unlimited exposure to sunlight. The patient was homoallelic for a novel URO-synthase missense mutation, G188R, that expressed less than 5% of mean normal activity in Escherichia coli, consistent with her transfusion dependency. Because the clinical severity of CEP is highly variable, ranging from nonimmune hydrops fetalis to milder, later onset forms with only cutaneous lesions, the importance of genotyping newly diagnosed infants to select severely affected patients for BMT is emphasized. In addition, the long-term effectiveness of BMT in this patient provides the rationale for future hematopoietic stem cell gene therapy in severely affected patients with CEP.     

Serum thrombomodulin levels in patients receiving allogeneic bone marrow transplantation

It has been reported that serum levels of thrombomodulin (TM) reflect endothelial damages in various diseases. We measured serum TM levels between day-10 and day 100 in 6 patients receiving allogeneic bone marrow transplantation. Serum TM levels were increased when patients had transplant related complications including graft versus host disease, hemorrhagic cystitis and interstitial pneumonitis. In patient without complications, serum TM levels were within normal limits. These results suggest that the serum TM level serves as a useful marker of treatment related toxicity and a predictor of complications after BMT.     

The effect of human leukocyte antigen disparity on cyclosporine neurotoxicity after allogeneic bone marrow transplantation

PURPOSE: We examined the relationship between human leukocyte antigen (HLA) matching and the development of cyclosporine (CyA) neurotoxicity in patients undergoing allogeneic bone marrow transplantation, and determined the frequency and imaging characteristics of CyA neurotoxicity in these patients. METHODS: Records of 87 patients who underwent allogeneic bone marrow transplantation were reviewed. Eight patients who presented with visual disturbance and/or seizures and had MR imaging within 24 hours were identified. Transplant donor relatedness was examined, and patients' imaging studies were reviewed. Clinical parameters, including blood pressure, CyA, creatinine, and magnesium levels, and the presence of graft-versus-host disease were reviewed. RESULTS: CyA neurotoxicity was seen more frequently in HLA-mismatched and unrelated donor transplants. The frequency of CyA neurotoxicity was 4% for patients with a 5/6 or 6/6 HLA match, 13% for matched unrelated donor transplants, and 50% for haplotypic 3/6 or 4/6 transplants. Patients with matched unrelated donor transplants and haplotypic transplants presented earlier in the posttransplant time course and had decreased survival time relative to patients with HLA-matched transplants. Imaging abnormalities most commonly affected the occipital lobes and the posterior cerebral hemispheres; both cortical and white matter involvement was identifiable as T1 hypointense and T2 hyperintense signal with associated gyral swelling and sulcal effacement on the initial MR studies. Hypodensity in the affected areas was noted on CT scans. Contrast enhancement was seen in HLA-mismatched and unrelated transplants only. Follow-up imaging showed interval decreases in subcortical edema; however, residual signal abnormality, primarily affecting the cortex, was present in all cases and seen best on proton density-weighted MR images. CONCLUSION: The frequency of severe CyA neurotoxicity increases with increasing HLA disparity, suggesting that immune factors may play a role. CyA neurotoxicity appears to represent a spectrum of disease processes. Disruption of the blood-brain barrier as well as hypoxic or vasculitic cortical injury resulting in MR-detectable cortical signal abnormalities may occur in severe cases.